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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Selective UBC 13 Inhibitors - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Selective UBC 13 Inhibitors">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2014/05/13">
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<meta name="citation_author" content="Robert Ardecky">
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<meta name="citation_author" content="Charitha Madiraju">
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<meta name="citation_author" content="Shu-ichi Matsuzawa">
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<meta name="citation_author" content="Jiwen Zou">
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<meta name="citation_author" content="Santhi Ganji">
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<meta name="citation_author" content="Ian Pass">
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<meta name="citation_author" content="Tram A. Ngo">
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<meta name="citation_author" content="Anthony B. Pinkerton">
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<meta name="citation_author" content="Eduard Sergienko">
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<meta name="citation_author" content="Ying Su">
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<meta name="citation_author" content="Derek Stonich">
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<meta name="citation_author" content="Arianna Mangravita-Novo">
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<meta name="citation_author" content="Michael Vicchiarelli">
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<meta name="citation_author" content="Danielle McAnally">
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<meta name="citation_author" content="Layton H. Smith">
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<meta name="citation_author" content="Jena Diwan">
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<meta name="citation_author" content="Thomas D.Y. Chung">
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<meta name="citation_author" content="Yasuko Matsuzawa">
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<meta name="citation_author" content="Carina Wimer">
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<meta name="citation_author" content="Paul W. Diaz">
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<meta name="citation_author" content="John C. Reed">
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<meta name="DC.Title" content="Selective UBC 13 Inhibitors">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Robert Ardecky">
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<meta name="DC.Contributor" content="Charitha Madiraju">
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<meta name="DC.Contributor" content="Shu-ichi Matsuzawa">
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<meta name="DC.Contributor" content="Jiwen Zou">
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<meta name="DC.Contributor" content="Santhi Ganji">
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<meta name="DC.Contributor" content="Ian Pass">
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<meta name="DC.Contributor" content="Tram A. Ngo">
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<meta name="DC.Contributor" content="Anthony B. Pinkerton">
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<meta name="DC.Contributor" content="Eduard Sergienko">
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<meta name="DC.Contributor" content="Ying Su">
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<meta name="DC.Contributor" content="Derek Stonich">
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<meta name="DC.Contributor" content="Arianna Mangravita-Novo">
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<meta name="DC.Contributor" content="Michael Vicchiarelli">
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<meta name="DC.Contributor" content="Danielle McAnally">
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<meta name="DC.Contributor" content="Layton H. Smith">
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<meta name="DC.Contributor" content="Jena Diwan">
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<meta name="DC.Contributor" content="Thomas D.Y. Chung">
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<meta name="DC.Contributor" content="Yasuko Matsuzawa">
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<meta name="DC.Contributor" content="Carina Wimer">
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<meta name="DC.Contributor" content="Paul W. Diaz">
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<meta name="DC.Contributor" content="John C. Reed">
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<meta name="DC.Date" content="2014/05/13">
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<meta name="description" content="This probe report describes the identification and development of a potent, sub-micromolar (IC50 = 781 nM), first-in-class, small molecule inhibitor of Ubc13 enzyme activity, ML307. The activity of the probe compound was assessed by its ability to suppress Ubc13-mediated formation of heteropolymeric poly-ubquitination chains comprised of a mix of terbium-labeled and fluorescein-labeled ubiquitin molecules, as monitored by a reduction of the time-resolved fluorescent resonance energy transfer (TR-FRET) signal arising from this chains when synthesized in vitro in collaboration with the Ubc13 cofactor UEV1a. ML307 has excellent solubility and stability in buffer and is not a general cysteine protease inhibitor as it is >128-fold selective against Caspase-3, nor a TR-FRET artifact as it is not inhibitory a TR-FRET assay for Bfl-1, an out of class target. ML307 resulted from an extensive elucidation of the structure-activity relationship (SAR) through the purchase and synthesis of over 90 compounds representing 5 related scaffolds. The level of in vitro potency achieved is unprecedented in the current state of art, thus representing a significant advance and providing a chemical tool for assessing the biological roles and biochemical mechanisms of Ubc13.">
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<meta name="og:description" content="This probe report describes the identification and development of a potent, sub-micromolar (IC50 = 781 nM), first-in-class, small molecule inhibitor of Ubc13 enzyme activity, ML307. The activity of the probe compound was assessed by its ability to suppress Ubc13-mediated formation of heteropolymeric poly-ubquitination chains comprised of a mix of terbium-labeled and fluorescein-labeled ubiquitin molecules, as monitored by a reduction of the time-resolved fluorescent resonance energy transfer (TR-FRET) signal arising from this chains when synthesized in vitro in collaboration with the Ubc13 cofactor UEV1a. ML307 has excellent solubility and stability in buffer and is not a general cysteine protease inhibitor as it is >128-fold selective against Caspase-3, nor a TR-FRET artifact as it is not inhibitory a TR-FRET assay for Bfl-1, an out of class target. ML307 resulted from an extensive elucidation of the structure-activity relationship (SAR) through the purchase and synthesis of over 90 compounds representing 5 related scaffolds. The level of in vitro potency achieved is unprecedented in the current state of art, thus representing a significant advance and providing a chemical tool for assessing the biological roles and biochemical mechanisms of Ubc13.">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK143542_"><span class="title" itemprop="name">Selective UBC 13 Inhibitors</span></h1><p class="contribs">Ardecky R, Madiraju C, Matsuzawa S, et al.</p><p class="fm-aai"><a href="#_NBK143542_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>This probe report describes the identification and development of a potent, sub-micromolar (IC<sub>50</sub> = 781 nM), first-in-class, small molecule inhibitor of Ubc13 enzyme activity, <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a>. The activity of the probe compound was assessed by its ability to suppress Ubc13-mediated formation of heteropolymeric poly-ubquitination chains comprised of a mix of terbium-labeled and fluorescein-labeled ubiquitin molecules, as monitored by a reduction of the time-resolved fluorescent resonance energy transfer (TR-FRET) signal arising from this chains when synthesized <i>in vitro</i> in collaboration with the Ubc13 cofactor UEV1a. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> has excellent solubility and stability in buffer and is not a general cysteine protease inhibitor as it is >128-fold selective against Caspase-3, nor a TR-FRET artifact as it is not inhibitory a TR-FRET assay for Bfl-1, an out of class target. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> resulted from an extensive elucidation of the structure-activity relationship (SAR) through the purchase and synthesis of over 90 compounds representing 5 related scaffolds. The level of <i>in vitro</i> potency achieved is unprecedented in the current state of art, thus representing a significant advance and providing a chemical tool for assessing the biological roles and biochemical mechanisms of Ubc13.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1R03MH-085677-01</p><p><b>Screening Center Name & PI:</b> Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute & John C. Reed, M.D., Ph.D.</p><p><b>Chemistry Center Name & PI:</b>
|
|
<i>Same as Screening Center</i></p><p><b>Assay Submitter & Institution:</b> John C. Reed, M.D., Ph.D. & Sanford-Burnham Medical Research Institute</p><p><b>PubChem Summary Bioassay Identifier (AID): <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485343" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">485343</a></b></p><div id="ml307.s1"><h2 id="_ml307_s1_">Probe Structure & Characteristics</h2><p>This Center Probe Report describes a small molecule inhibitor of Ubc13, compound <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a>, <b>CID 56639556 (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134958980</a>).</b> Potency, and selectivity characteristics are summarized for this probe in the next section, while the Absorption, Distribution, Metabolism, Excretion/Toxicity (ADME/T) are profiled in <a class="figpopup" href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object" rid-figpopup="figml307t8" rid-ob="figobml307t8">Table 8</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t8"><a href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object" title="Table 8" class="img_link icnblk_img figpopup" rid-figpopup="figml307t8" rid-ob="figobml307t8"><img class="small-thumb" src="/books/NBK143542/table/ml307.t8/?report=thumb" src-large="/books/NBK143542/table/ml307.t8/?report=previmg" alt="Table 8. Summary of in vitro ADME Properties of UBC13 inhibitor probe ML307." /></a><div class="icnblk_cntnt"><h4 id="ml307.t8"><a href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object" rid-ob="figobml307t8">Table 8</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME Properties of UBC13 inhibitor probe ML307. </p></div></div><div id="ml307.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu1.jpg" alt="ML307." /></div><h3><span class="title">ML307</span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307tu1"><a href="/books/NBK143542/table/ml307.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml307tu1" rid-ob="figobml307tu1"><img class="small-thumb" src="/books/NBK143542/table/ml307.tu1/?report=thumb" src-large="/books/NBK143542/table/ml307.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml307.tu1"><a href="/books/NBK143542/table/ml307.tu1/?report=objectonly" target="object" rid-ob="figobml307tu1">Table</a></h4></div></div></div><div id="ml307.s2"><h2 id="_ml307_s2_">Recommendations for scientific use of the probe</h2><p>Currently, no publically available small molecule Ubc13 Probes exist that have submicromolar potency (IC<sub>50</sub>) against the target protein as measured by <i>in vitro</i> biochemical assays and are at least 10-fold selective for Ubc13 over irrelevant targets or functionally similar targets such as other E2 enzymes. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> will be useful for elucidating the enzymology of Ubc13, the effects of specific inhibition of Ubc13 versus other E2, and mapping the active site of Ubc13 or the Ubc13-Uev1a interface. Such probes will be useful for specifically modulating Ubc13-dependent cellular functions. Ubc13 is the only mammalian E2 enzyme known that catalyzes exclusively the formation of lysine 63 (K63)-linked polyubiquitin chains on substrates. Such K63-linked polyubiquitination modifications are associated with novel cellular functions, including innate immunity (inflammation) signaling and DNA damage repair. The probes therefore will be very useful to researchers exploring immunomodulation and inflammation as well as those in the fields of cancer biology and radiobiology. Finally, the larger research community who studies Ubc13 and ubiquitination-regulated pathways will certainly be beneficiaries of such chemical inhibitors.</p></div><div id="ml307.s3"><h2 id="_ml307_s3_">1. Introduction</h2><p>This probe project aimed to generate small molecule antagonists of Ubc13 and to distinguish compounds that attack at the active site from those that interrupt the Ubc13-Uev1a interface.</p><div id="ml307.s4"><h3>Specific Aims</h3><p><b><i>Aim #1.</i></b> Screen a library of chemicals employing a TR-FRET-based ubiquitination assay. An <i>in vitro</i> ubiquitination assay based on the TR-FRET assay principle was established for Ubc13. Ubiquitination reactions contain purified recombinant proteins (E1, Ubc13 and Uev1a) mixed with labeled ubiquitin (terbium- and fluorescein-labeled) and ATP-regenerating system to trigger polyubiquitin chain synthesis <i>in vitro</i>. The reaction product is mixed chains of terbium- (fluorescence donor) and fluorescein- (fluorescence acceptor) conjugated Ubiquitin, thus creating the basis for robust TR-FRET signals.</p><p><b><i>Aim #2.</i></b> Perform counter-screens to eliminate false-positive compounds from screening hits. Redox modulating compounds could intervene with ubiquitination reaction process by their potential to bind the active site thiol-containing cysteine residue of Ubc13. Hence, primary hits will be re-tested in with a GAPDH assay (an enzyme that also possesses a catalytic cysteine) to eliminate redox-active compounds. Next, a TR-FRET previously established in our laboratory for an entirely different target (Bcl-XL) will be used to eliminate compounds that non-specifically interfere with the FRET-based reaction. Then, an <i>in vitro</i> ubiquitination assay for an alternative E2 and E3 system (Siah/UbcH5) will be counter-screened, thus eliminating compounds that interfere with E1 or with classical E2 enzymes. Finally, compounds will be tested by micro-isothermal titration calorimetry, high throughput surface plasmon resonance (SPR), for 1D-NMR to establish that they bind directly to either Ubc13 or its cofactor Uev1a.</p><p><b><i>Aim #3.</i></b> Perform cell-based secondary assays to validate chemical hits. Two types of secondary cell-based assays will be performed to validate the hits. First, it has been determined by RNA interference (RNAi) experiments that Interleukin-1β stimulates NF-κB activity through a Ubc13-dependent mechanism in U2OS cells. We have stably integrated a NF-κB-driven luciferase reporter gene into U2OS cells and will use these cells to determine the cellular activity of the Ubc13 inhibitors. Second, we are developing a cell-based, secondary assay using bioluminescent resonance energy transfer (BRET), in which fusion proteins <i>Rluc</i>-TRAF6 and YFP-Ubiquitin are co-expressed in cells. Stimulation with cytokines or other agents that activate TRAF6 induce formation of K63-linked polyubiquitin chains on TRAF6. Addition of luciferase substrate generates light, which then excites the YFP, producing the signal for the assay.</p></div><div id="ml307.s5"><h3>Background and Significance</h3><p>Innate immunity signaling events are often initiated by Toll-like receptors (TLRs) and Tumor Necrosis Factor (TNF) family receptors. The intracellular signaling pathways activated by TLRs and TNFRs converge on TRAF family adaptor proteins (<a class="bibr" href="#ml307.r1" rid="ml307.r1">1</a>). TRAFs bind to the cytosolic tails of TNFRs or are recruited to TNFRs and TLR (and IL-1Rs) through other adapter proteins (<a class="bibr" href="#ml307.r2" rid="ml307.r2">2</a>–<a class="bibr" href="#ml307.r5" rid="ml307.r5">5</a>). Importantly, TRAFs are also involved in signaling by T-cell and B-cell antigen receptors (TCR/BCR) in a pathway involving Carma1, Bcl-10, and paracaspase (MALT1) to induce nuclear factor κB (NF-κB) (<a class="bibr" href="#ml307.r6" rid="ml307.r6">6</a>–<a class="bibr" href="#ml307.r8" rid="ml307.r8">8</a>). TRAFs are known to activate specific protein kinases, which in turn activate NF-κB, AP-1, and NFAT proteins (nuclear factor of activated T cells), which are required for induction and expression of lymphokines, lymphokine receptors, and other mediators of immunity (<a class="bibr" href="#ml307.r7" rid="ml307.r7">7</a>,<a class="bibr" href="#ml307.r9" rid="ml307.r9">9</a>–<a class="bibr" href="#ml307.r13" rid="ml307.r13">13</a>). It was shown, in autoimmune diseases, that TNF-receptor associated factors (TRAFs) are crucial participants in cytokine signaling pathways leading to NF-κB activation and proinflammatory cytokine production (<a class="bibr" href="#ml307.r13" rid="ml307.r13">13</a>,<a class="bibr" href="#ml307.r14" rid="ml307.r14">14</a>).</p><p>TRAFs undergo post-translational modification <i>via</i> an unusual ubiquitination process that is a requirement for triggering activation of downstream kinases (<a class="bibr" href="#ml307.r1" rid="ml307.r1">1</a>). Like many other E3 ligases, most TRAFs (five of six in humans and mice) possess RING domains and auto-ubiquitinate themselves. The RING domain of TRAFs binds a specific ubiquitin-conjugating enzyme, Ubc13, which catalyzes the synthesis of polyubiquitin chains on TRAFs (<a class="bibr" href="#ml307.r15" rid="ml307.r15">15</a>,<a class="bibr" href="#ml307.r16" rid="ml307.r16">16</a>,<a class="bibr" href="#ml307.r17" rid="ml307.r17">17</a>–<a class="bibr" href="#ml307.r19" rid="ml307.r19">19</a>), in addition to protein kinase substrates of TRAFs. However, the polyubiquitin chains created by Ubc13 do not target TRAFs or their substrates for proteasomal degradation. Instead, the ubiquitin modifications activate the proteins, inducing downstream signaling events, including activation of NF-κB and MAPK-family kinases.</p><p>In eukaryotic cells, the chemistry of ubiquitination relies on the dynamic interaction of ubiquitin (Ub) with three different classes of enzymes, termed ubiquitin-activating enzyme (E1), ubiquitin conjugating enzyme (E2), and ubiquitin ligase (E3) (<a class="bibr" href="#ml307.r20" rid="ml307.r20">20</a>). The canonical pathway of ubiquitination leading to degradation of ubiquitinylated proteins by the proteasome involves a covalent attachment of Gly76 at the C-terminus of Ub with the ɛ-amino group of LYS48 of another Ub to form a polyubiquitin chain. However, in the case of Ubc13, LYS63, instead of LYS48, is used as the site for linking Ub chains. This K63-linked polyubiquitinylation reaction is catalyzed by Ubc13 in complex with its non-enzymatic cofactors Mms2 or Uev1a (<a class="bibr" href="#ml307.r15" rid="ml307.r15">15</a>,<a class="bibr" href="#ml307.r21" rid="ml307.r21">21</a>). Mms2 is predominantly nuclear while Uev1a is predominantly cytosolic. NMR and crystallography studies have revealed the structures of Ubc13, its catalytic site, and its interface with these obligatory co-factor proteins (<a class="bibr" href="#ml307.r13" rid="ml307.r13">13</a>,<a class="bibr" href="#ml307.r22" rid="ml307.r22">22</a>–<a class="bibr" href="#ml307.r25" rid="ml307.r25">25</a>). In this regard, structural studies of Ubc13-Mms2 and Ubc13-Uev1a complexes show a deep, narrow and long hydrophobic binding pocket at the interface of Ubc13-Uev1a. However, Mms2 and Uev1a differ in their sequences at the N-terminus end and are known to differentially regulate cellular processes (<a class="bibr" href="#ml307.r26" rid="ml307.r26">26</a>). While the non-covalent interaction of Ubc13-Mms2 is necessary for cellular mechanisms involving DNA damage repair, the Ubc13-Uev1a complex regulates inflammatory and immune signaling pathways. However, Ubc13 also mediates NF-κB activation induced by DNA damage, a process for which the co-factor has not be defined.</p><p>Recently, gene ablation studies in mice have validated Ubc13, as a candidate target for autoimmune and inflammatory diseases (<a class="bibr" href="#ml307.r27" rid="ml307.r27">27</a>). Homozygous disruption of the <i>Ubc13</i> gene results in embryonic lethality. Also, tissue-specific homozygous ablation of both alleles of the <i>Ubc13</i> gene in B-cells results in defective development of marginal B and B1 cells along with impairment of humoral response. However, the Assay Provider’s laboratory has produced hemizygous <i>Ubc13</i> mice (<i>Ubc13</i>+/−), observing that reduced levels of Ubc13 protein are associated with significantly impaired signaling by TNF and lipopolysaccharide (LPS), resulting in reduced TRAF ubiquitination <i>in vivo</i>, and reduced activation of NF-κB and stress kinases (p38 MAPK and JNK) <i>in vivo</i> (<a class="bibr" href="#ml307.r28" rid="ml307.r28">28</a>). These hemizygous <i>Ubc13</i>+/− mice are phenotypically normal in all respects, including various lymphocyte subpopulations. Because the TNFR, TLR, and TCR/BCR signaling pathways all depend on TRAFs, targeting the TRAF-associated Ubc13-Uev1a complex would be expected to interrupt inflammatory signaling and quiet the immune system. Biochemical and structural studies of Ubc13 and Ubc13-Uev1a complex lay the foundation for design of small molecule inhibitors that are expected to have potent anti-inflammatory and immunosuppressive activity for treatment of immune diseases. In addition, because of its role in double-strand DNA break repair and NF-κB signaling induced by DNA damage (which stimulates transcription of multiple anti-apoptotic, pro-survival genes), inhibition of Ubc13 would also potentially be beneficial for cancer therapy.</p></div><div id="ml307.s6"><h3>Prior Art</h3><p>The ideal probe has a potency ≤100 nM for the biochemical Ubc13 assay and has at least a 10 μM potency in a Ubc13-dependent cell assay. Additionally it would be desirable for the probe to be ≥ 10-fold selective for Ubc13 over other E2 enzymes and similar classes of cysteine-dependent enzymes. No publically available and potent Ubc13 Probes exist that meet these criteria.</p><p>A non-drug-like, natural product compound that inhibits the formation of a complex composed of the ubiquitin E2 enzyme Ubc13 and Uev1A was isolated from the marine sponge <i>Leucetta Microrhaphis</i> (<a class="figpopup" href="/books/NBK143542/figure/ml307.f1/?report=objectonly" target="object" rid-figpopup="figml307f1" rid-ob="figobml307f1">Figure 1</a>). The compound was identified as leucettamol A (<u><b>1</b></u>) by spectroscopic analysis. Its inhibition of Ubc13-Uev1A interaction was tested by the ELISA method, revealing an IC<sub>50</sub> value of 50 μg/mL. The compound is the first reported inhibitor of Ubc13-Uev1A interaction, and that of the E2 activity of Ubc13. The inhibition of Ubc13-Uev1A interaction was tested in an ELISA assay according to standard procedures (<i>see</i> Bioorganic & Medicinal Chemistry Letter (2008) <b>18:</b> 6319–6320) using purified recombinant Ubc13 and FLAG-Uev1A proteins and a primary anti-FLAG antibody (SIGMA, F3165) and found to be very weak for compound <u><b>1</b></u> with an estimated IC<sub>50</sub> value of 50 μg/mL (~110 μM; m.w. 472). The isolated compounds <u><b>1</b></u> and <u><b>3</b></u> are not stable and isomerize readily. This publication also notes that hydrogenation of <u><b>1</b></u> increases its potency to ~ 4 μg/mL (~8 μM), while <u><b>3</b></u> is completely inactive. However, testing of the reported compound in the Assay Provider’s laboratory failed to reveal detectable activity against Ubc13.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml307f1" co-legend-rid="figlgndml307f1"><a href="/books/NBK143542/figure/ml307.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml307f1" rid-ob="figobml307f1"><img class="small-thumb" src="/books/NBK143542/bin/ml307f1.gif" src-large="/books/NBK143542/bin/ml307f1.jpg" alt="UBC13 Prior Art" /></a><div class="icnblk_cntnt" id="figlgndml307f1"><h4 id="ml307.f1"><a href="/books/NBK143542/figure/ml307.f1/?report=objectonly" target="object" rid-ob="figobml307f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Natural Product Prior Art compounds. Compound (1) is registered in PubChem – See SIDs therein </p></div></div><p>A patent (WO2008/009758) describes compounds claimed to inhibit UBC13-UEV interactions and for use in the production of pharmaceutical compositions intended for antitumor therapy or the treatment and/or prophylaxis of diseases associated with metabolic routes involving the UBC13 enzyme, metabolic routes involving transcriptional factor NF-κB or routes involving PCNA or RAD6. The compounds from this patent are listed (<a class="figpopup" href="/books/NBK143542/figure/ml307.f2/?report=objectonly" target="object" rid-figpopup="figml307f2" rid-ob="figobml307f2">Figure 2</a>.). However, the patents do not provide any potency information:</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml307f2" co-legend-rid="figlgndml307f2"><a href="/books/NBK143542/figure/ml307.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml307f2" rid-ob="figobml307f2"><img class="small-thumb" src="/books/NBK143542/bin/ml307f2.gif" src-large="/books/NBK143542/bin/ml307f2.jpg" alt="UBC13 Prior Art 2" /></a><div class="icnblk_cntnt" id="figlgndml307f2"><h4 id="ml307.f2"><a href="/books/NBK143542/figure/ml307.f2/?report=objectonly" target="object" rid-ob="figobml307f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Prior Art compounds described in Patent for UBC13/UEV. PubChem CID for the described compounds are noted </p></div></div></div></div><div id="ml307.s7"><h2 id="_ml307_s7_">2. Materials and Methods</h2><p>The details of the primary HTS and additional assays can be found in the “Assay Description” section in the PubChem BioAssay view under the AIDs as listed in <a class="figpopup" href="/books/NBK143542/table/ml307.t1/?report=objectonly" target="object" rid-figpopup="figml307t1" rid-ob="figobml307t1">Table 1</a>. Additionally the details for the primary HTS are provided in the Appendix at the end of this probe report.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t1"><a href="/books/NBK143542/table/ml307.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml307t1" rid-ob="figobml307t1"><img class="small-thumb" src="/books/NBK143542/table/ml307.t1/?report=thumb" src-large="/books/NBK143542/table/ml307.t1/?report=previmg" alt="Table 1. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml307.t1"><a href="/books/NBK143542/table/ml307.t1/?report=objectonly" target="object" rid-ob="figobml307t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div><div id="ml307.s8"><h3>2.1. Assays</h3><p><a class="figpopup" href="/books/NBK143542/table/ml307.t1/?report=objectonly" target="object" rid-figpopup="figml307t1" rid-ob="figobml307t1">Table 1</a> summarizes the details for the assays that drove this probe project.</p></div><div id="ml307.s9"><h3>2.2. Probe Chemical Characterization</h3><div id="ml307.s10"><h4>a. Chemical name of probe compound</h4><p>The IUPAC name of the probe <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is (R)-N-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)-1-(6,7,8,9-tetrahydropyrido[1,2-e]purin-4-yl)piperidine-3-carboxamide. The actual batch prepared, tested and submitted to MLSMR is <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134958980</a> corresponding to CID 56639556.</p></div><div id="ml307.s11"><h4>b. Probe chemical structure including stereochemistry if known</h4><p>The probe molecule CID 56639556 has one chiral center and that center has the <b>R</b> conformation (<a class="figpopup" href="/books/NBK143542/figure/ml307.f3/?report=objectonly" target="object" rid-figpopup="figml307f3" rid-ob="figobml307f3">Figure 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml307f3" co-legend-rid="figlgndml307f3"><a href="/books/NBK143542/figure/ml307.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml307f3" rid-ob="figobml307f3"><img class="small-thumb" src="/books/NBK143542/bin/ml307f3.gif" src-large="/books/NBK143542/bin/ml307f3.jpg" alt="Figure 3. Structure of ML307." /></a><div class="icnblk_cntnt" id="figlgndml307f3"><h4 id="ml307.f3"><a href="/books/NBK143542/figure/ml307.f3/?report=objectonly" target="object" rid-ob="figobml307f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Structure of ML307. Note R-configuration stereochemistry as indicated around the 3-position of the piperdine ring. </p></div></div></div><div id="ml307.s12"><h4>c. Synthesis and Structural Verification Information of probe SID 134958980 <i>corresp</i>onding to CID 56639556 (<i>See</i>
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<a class="figpopup" href="/books/NBK143542/figure/ml307.f6/?report=objectonly" target="object" rid-figpopup="figml307f6" rid-ob="figobml307f6">Scheme 1</a>)</h4><div id="ml307.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%201.%20Synthesis%20of%20ML307%2C%20conditions.&p=BOOKS&id=143542_ml307f6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK143542/bin/ml307f6.jpg" alt="Scheme 1. Synthesis of ML307, conditions." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML307, conditions</span></h3><div class="caption"><p><b>a</b>. DMF, 113 °C, overnight (46%); <b>b</b>. Triethylorthoformate, DMF, 150 °C, overnight (58%); <b>c</b>. POCl<sub>3,</sub> CH<sub>3</sub>CN, 90 °C (59%); <b>d</b>. DIPEA, DCM, rt, overnight; <b>e</b>.4M HCl, Dioxane (60%, 2 steps); <b>f</b>. EDCI, HOBT, DIPEA, DMF, rt, overnight (53%); <b>g</b>. 10% TFA, DCM (100%); <b>h</b>. K<sub>2</sub>CO<sub>3,</sub> CH<sub>3</sub>CN, 80 °C (54%).</p></div></div></div><div id="ml307.s13"><h4>d. If available from a vendor, please provide details</h4><p>This probe is not commercially available. A 25 mg sample of <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> synthesized at SBCCG has been deposited in the MLSMR (Evotec) (see Probe Submission <a class="figpopup" href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object" rid-figpopup="figml307t4" rid-ob="figobml307t4">Table 4</a>).</p></div><div id="ml307.s14"><h4>e. Solubility and Stability of probe in PBS at room temperature</h4><p>The solubility of <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> was investigated in aqueous buffers at room temperature. As noted in the <i>Summary of</i>
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<b><i>in vitro</i></b>
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<i>ADME/T properties</i> (see <a class="figpopup" href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object" rid-figpopup="figml307t8" rid-ob="figobml307t8">Table 8</a>), <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> has excellent solubility relative to its potency against UBC13 in aqueous buffer at all pH’s tested: 348, 351 and 373 μM, at pH 5, 6.2, and 7.4 in pION buffer, and 352μM in PBS, which are 446-, 449-, 478- and 451-fold its potency (0.781 μM) against UBC13. To evaluate its potential hydrolytic instability an aliquot of <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> was prepared in PBS or a acetonitrile:PBS (1:1) mixture and incubated at room temperature, and the amounts of the parent compound remaining at various times were analyzed by LC/MS (<a class="figpopup" href="/books/NBK143542/figure/ml307.f4/?report=objectonly" target="object" rid-figpopup="figml307f4" rid-ob="figobml307f4">Figure 4</a> time course and <a class="figpopup" href="/books/NBK143542/table/ml307.t2/?report=objectonly" target="object" rid-figpopup="figml307t2" rid-ob="figobml307t2">Table 2</a>). The results here and in <a class="figpopup" href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object" rid-figpopup="figml307t8" rid-ob="figobml307t8">Table 8</a> indicate that <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is very stable with 80.5% and 100% remaining after incubation for 48 hrs at ambient temperatures in PBS or 1:1 PBS:acetonitrile, respectively.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml307f4" co-legend-rid="figlgndml307f4"><a href="/books/NBK143542/figure/ml307.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml307f4" rid-ob="figobml307f4"><img class="small-thumb" src="/books/NBK143542/bin/ml307f4.gif" src-large="/books/NBK143542/bin/ml307f4.jpg" alt="Figure 4. Stability of ML307 in (△) PBS or (●) 1:1 acetonitrile:PBS at room temperature." /></a><div class="icnblk_cntnt" id="figlgndml307f4"><h4 id="ml307.f4"><a href="/books/NBK143542/figure/ml307.f4/?report=objectonly" target="object" rid-ob="figobml307f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Stability of ML307 in (△) PBS or (●) 1:1 acetonitrile:PBS at room temperature. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t2"><a href="/books/NBK143542/table/ml307.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml307t2" rid-ob="figobml307t2"><img class="small-thumb" src="/books/NBK143542/table/ml307.t2/?report=thumb" src-large="/books/NBK143542/table/ml307.t2/?report=previmg" alt="Table 2. Hydrolytic stability of ML307 at ambient temperature." /></a><div class="icnblk_cntnt"><h4 id="ml307.t2"><a href="/books/NBK143542/table/ml307.t2/?report=objectonly" target="object" rid-ob="figobml307t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Hydrolytic stability of <i>ML307</i> at ambient temperature. </p></div></div></div><div id="ml307.s15"><h4>f. Calculated and known probe properties: are shown in <a class="figpopup" href="/books/NBK143542/table/ml307.t3/?report=objectonly" target="object" rid-figpopup="figml307t3" rid-ob="figobml307t3">Table 3</a></h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t3"><a href="/books/NBK143542/table/ml307.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml307t3" rid-ob="figobml307t3"><img class="small-thumb" src="/books/NBK143542/table/ml307.t3/?report=thumb" src-large="/books/NBK143542/table/ml307.t3/?report=previmg" alt="Table 3. CID 56639556 [ML307] MLS-0471611." /></a><div class="icnblk_cntnt"><h4 id="ml307.t3"><a href="/books/NBK143542/table/ml307.t3/?report=objectonly" target="object" rid-ob="figobml307t3">Table 3</a></h4><p class="float-caption no_bottom_margin">CID 56639556 [ML307] MLS-0471611. </p></div></div></div><div id="ml307.s16"><h4>g. <a class="figpopup" href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object" rid-figpopup="figml307t4" rid-ob="figobml307t4">Table 4</a> summarizes the deposition of the Probe and 5 analogs</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t4"><a href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml307t4" rid-ob="figobml307t4"><img class="small-thumb" src="/books/NBK143542/table/ml307.t4/?report=thumb" src-large="/books/NBK143542/table/ml307.t4/?report=previmg" alt="Table 4. Probe and Analog Submissions to MLSMR (BioFocus DPI) for UBC13 Inhibitors." /></a><div class="icnblk_cntnt"><h4 id="ml307.t4"><a href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object" rid-ob="figobml307t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to MLSMR (BioFocus DPI) for UBC13 Inhibitors. </p></div></div></div></div><div id="ml307.s17"><h3>2.3. Probe Preparation</h3><p>The preparation of the probe molecule <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> was moderately difficult. Compound <b>5</b> is commercially available but the cost of the starting material $5000 for 1 gram with a 12-week delivery date, forced us to synthesize this molecule in our laboratories. The synthetic route to this molecule is straightforward but the intermediates compounds <b>3</b> and <b>4</b> are very insoluble molecules. Purification of these molecules by either silica gel or C-18 HPLC liquid chromatography resulted in the isolation of miniscule amounts of the desired intermediates. Based upon these findings, it was decided to carry through the impure compounds <b>3</b> and <b>4</b> and purify at a later stage of the synthesis. It should be noted that in the preparation of compound <b>4</b>, triethylorthoformate was used as a co-solvent otherwise the reaction would not proceed to completion. Fortunately for us, Compound <b>5</b> was isolated cleanly as an orange solid after trituration of the crude product with acetone. The synthesis of <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> proceeded smoothly with known chemistry after we synthesized compound <b>5</b>.</p><p><b>Experimental</b>: (compounds are numbers as in <a class="figpopup" href="/books/NBK143542/figure/ml307.f6/?report=objectonly" target="object" rid-figpopup="figml307f6" rid-ob="figobml307f6">Scheme 1</a>)</p><div id="ml307.s18"><h4>Preparation of 3-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide [3]</h4><div id="ml307.fu2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu2.jpg" alt="3." /></div><h3><span class="title">3</span></h3></div><p>2-amino-2-cyanoacetamide <b>1</b> (6.1 g, 62 mmol) and o-methylvalerolactam <b>2</b> (7.0 g, 62 mmol) was dissolved in 200 ml of DMF. The resulting mixture was heated at 113 °C overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was triturated with ethanol or acetone and filtered to yield 5.1 g of dark brown crude product <b>3</b> (46 % yield). MS(EI) m/z 181 (M+1).</p></div><div id="ml307.s19"><h4>Preparation of 6,7,8,9-tetrahydropyrido[1,2-e]purin-4-ol [4]</h4><div id="ml307.fu3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu3.jpg" alt="4." /></div><h3><span class="title">4</span></h3></div><p>3-amino-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxamide <b>3</b> (5.1 g, 28.3 mmol) and triethylorthoformate (100 g, 0.68 mol) was dissolved in 100 ml of DMF. The resulting mixture was heated at 150 °C overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was triturated with ethanol or acetone and filtered to yield 3.1 g of a dark brown crude product <b>4</b> (58 % yield). MS(EI) m/z 191 (M+1).</p></div><div id="ml307.s20"><h4>Preparation of 4-chloro-6,7,8,9-tetrahydropyrido[1,2-e]purine [5]</h4><div id="ml307.fu4" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu4.jpg" alt="5." /></div><h3><span class="title">5</span></h3></div><p>Phosphorus oxychloride POCl<sub>3</sub> (50 mL, 0.20 mol) was added drop wise to a solution of 6,7,8,9-tetrahydropyrido[1,2-e]purin-4-ol 4 (3.1 g, 16.3 mmol) in dry acetonitrile (50 mL) to give an dark solution, then several drops of DMF was added if necessary. The reaction was heated at 90 °C overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was basified with 1N NaOH solution, extracted with ethyl acetate and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure, triturated with acetone, filtered and dried to give 2.0 g of compound <b>5</b> (59% yield). <sup>1</sup>H NMR (400 MHz, CDCl3) δ 2.08 (m, 2H), 2.15 (m, 2H), 3.17(t, 2H), 4.23 (t, 2H), 8.66 (s, 1H). MS(EI) m/z 209 (M+1).</p></div><div id="ml307.s21"><h4>Preparation of (1-(3-chlorobenzyl)piperidin-4-yl)methanamine [8]</h4><div id="ml307.fu5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu5.jpg" alt="8." /></div><h3><span class="title">8</span></h3></div><p>To a solution of 4-Boc-(aminomethyl)piperdine <b>6</b> (2.14 g, 1.0 mmol) and 3-chlorobenzyl bromide <b>7</b> (2.1 g, 1.0 mmol) in anhydrous dichloromethane(100 ml) was added 2.0 mL of DIPEA. The reaction mixture was stirred at room temperature overnight. The resulting mixture was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give an oil, which was purified by preparative C-18 reverse phase HPLC to give a white solid. The solid was deprotected with 4 M HCl in dioxane to 0.4 g of compound <b>8</b> (HCl salt<b>,</b> 60% yield, 2 steps). <sup>1</sup>H NMR (400 MHz, DMSO-d) δ 1.37 (m, 2H), 1.77 (m, 1H), 1.88 (m, 2H), 2.48 (m, 1H), 2.66 (m, 2H), 2.89 (m, 2H), 3.10 (m, 1H), 3.33 (m, 2H), 4.24 (s, 2H), 7.40 (m, 3H), 7.55 (m, 1H). MS(EI) m/z 239 (M+1).</p></div><div id="ml307.s22"><h4>Preparation of (R)-N-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)piperidine-3-carboxamide [10]</h4><div id="ml307.fu6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu6.jpg" alt="10." /></div><h3><span class="title">10</span></h3></div><p>To a solution of (1-(3-chlorobenzyl)piperidin-4-yl)methanamine 7 (1.2 g, 5.0 mmol) and (R)-1-(<i>tert-</i>butoxycarbonyl)piperidine-3-carboxylic acid (1.2 g, 5.2 mmol) in anhydrous DMF(50 ml) was added 1.0 mL of DIPEA, EDCI (1.6 g, 8.4 mmol) and HOBT (1.1 g, 8.1 mmol). The reaction mixture was stirred at room temperature overnight. When the reaction was determined to be complete by HPLC, the reaction solution was concentrated under reduced pressure to give an oil. The oil was dissolved in 100 ml of ethyl acetate and washed with 1N NaOH solution and water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to get 1.2 g of a white solid (53% yield), which was deprotected with 10% TFA in dichloromethane to afford the compound <b>10</b> (TFA salt). <sup>1</sup>H NMR (400 MHz, DMSO-d) δ 1.35 (m, 2H), 1.60 (m, 1H), 1.63 (m, 2H), 1.75 (m, 3H), 1.79 (m, 1H), 2.49 (m, 1H), 2.88 (m, 5H), 2.90 (m, 1H), 3.16 (m, 2H), 3.32 (m, 2H), 4.27 (s, 2H), 7.47 (m, 3H), 7.60 (m, 1H). MS(EI) m/z 350 (M+1).</p></div><div id="ml307.s23"><h4>Preparation of (R)-N-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)-1-(6,7,8,9-tetrahydropyrido-[1,2-e]purin-4-yl)piperidine-3-carboxamide [11]</h4><div id="ml307.fu7" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu7.jpg" alt="11." /></div><h3><span class="title">11</span></h3></div><p>Potassium carbonate (1.5 g, 11 mmol)) was added to a solution of 4-chloro-6,7,8,9-tetrahydropyrido[1,2-e]purine <b>5</b> (500 mg, 2.4 mmol) and (R)-N-((1-(3-chlorobenzyl)piperidin-4-yl)methyl)piperidine-3-carboxamide <b>10</b> (0.95 g, 2.7 mmol) in acetonitrile (50 ml). The reaction was heated at 80 °C overnight. When the reaction was determined to be complete by HPLC, the reaction mixture was cooled to room temperature and filtered to give a solution, which was purified by preparative C-18 reverse phase HPLC to afford 0.67 g of compound <b>11</b> (54% yield). <sup>1</sup>H NMR (400 MHz, CDCl3) δ 1.32 (m, 2H), 1.50 (m, 1H), 1.63 (m, 4H), 1.84 (m, 2H), 2.02 (m, 6H), 2.22 (m, 2H), 2.54 (m, 1H), 2.95 (m, 4H), 3.10 (m, 2H), 3.55 (m, 2H), 4.10 (m, 4H), i4.32 (m, 2H), 7.32 (m, 4H), 8.27 (s, 1H). MS(EI) m/z 522 (M+1).</p></div></div></div><div id="ml307.s24"><h2 id="_ml307_s24_">3. Results</h2><p>The NIH collection was screened against the Ubc13 TR-FRET assay and confirmed hits were screened against Caspase-3 to remove general cysteinyl protease inhibitors, and Bfl-1 to weed out those artifacts inhibiting the TR-FRET assay irrespective of the Ubc13 target. Ultimately, from this hit triage, five related scaffolds were advance for further chemical optimization and SAR elucidation.</p><div id="ml307.s25"><h3>3.1. Summary of Screening Results</h3><p>The flow chart (<a class="figpopup" href="/books/NBK143542/figure/ml307.f5/?report=objectonly" target="object" rid-figpopup="figml307f5" rid-ob="figobml307f5">Figure 5</a>) summarizers the screening process used for the Ubc13 inhibitor campaign. Initial active compounds were identified following primary HTS of approximately 330,000 Molecular Libraries Small Molecules Repository (MLSMR) compounds at 20 μM using the Ubc13 TR-FRET Assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485273" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 485273</a>), 1,547 initial actives (~0.47% hit rate) were obtained. Compounds were deemed to be positive if they had 45% activity and an acceptable fluorescence profile defined as an F-Ratio >0.5 AND <1.5. This ratio allows for the analysis of normalized fluorescence (F) in a plate well with a compound comparing to control wells. It is calculated as a fluorescence ratio of the reference channel in TR-FRET. This filter effectively eliminates compounds that inherently alter the fluorescent properties of TR-FRET.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml307f5" co-legend-rid="figlgndml307f5"><a href="/books/NBK143542/figure/ml307.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml307f5" rid-ob="figobml307f5"><img class="small-thumb" src="/books/NBK143542/bin/ml307f5.gif" src-large="/books/NBK143542/bin/ml307f5.jpg" alt="Figure 5. Screening results and Hit validation." /></a><div class="icnblk_cntnt" id="figlgndml307f5"><h4 id="ml307.f5"><a href="/books/NBK143542/figure/ml307.f5/?report=objectonly" target="object" rid-ob="figobml307f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Screening results and Hit validation. </p></div></div><p>Fresh stock solutions “cherry picks” of these 1,547 hits were requested from the MLSMR (Biofocus DPI) and 1,430 were received (92.4%). These were then retested in the Ubc13 TR-FRET confirmatory assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488859" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488859</a>) at 20 μM. For the single point re-confirmatory assay, a cutoff of 45% inhibition and an F-Ratio >0.5 AND <1.5. yielded an 87% reconfirm rate resulting in a total of 1,245 compounds. To triage this hit set these hits were subjected to a sulfhydryl (Caspase-3) counterscreen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488856" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488856</a>), this filter is designed to remove promiscuous compounds for the common site of activity for Ubc13. This filter excluded a total of 35 compounds. The activities (IC<sub>50</sub>) of the remaining 1,210 compounds were confirmed in full 10-point dose-response titrations (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493155" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493155</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493182" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493182</a>). Of the 1,210 compounds tested a total of 296 compounds displayed activity with IC<sub>50</sub> values below 20 μM. These compounds were then further scrutinized for potential promiscuous LanthaScreen assay interference using an unrelated protein, Bfl-1 (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504689" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504689</a>), this further excluded 59 compounds. This collection of 251 compounds comprised of 43 scaffolds, with 2 or more examples and 83 singletons. Continued investigation focused on the most potent compounds with IC<sub>50</sub> values less than 5 μM. Of these 72 compounds, several of them contained chemical liabilities, i.e. Michael acceptor, frequent hitters, quinones, detergents, etc. and were eliminated from consideration. Based on these experimental results and informatic analysis, dry powder compounds were selected for follow up studies and additional, commercially available analogues were ordered.</p></div><div id="ml307.s26"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml307.fu8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu8.jpg" alt="Representative Dose Response of ML307 in the Ubc13 TR-FRET, Caspase-3 and Bfl-1 Assays." /></div><h3><span class="title">Representative Dose Response of ML307 in the Ubc13 TR-FRET, Caspase-3 and Bfl-1 Assays</span></h3></div></div><div id="ml307.s27"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>Neither the scaffold of the selected probe, nor the related scaffolds (<b>A, B, C, D & E</b>) contain any groups associated with any chemical liabilities or reactivities.</p></div><div id="ml307.s28"><h3>3.4. SAR Tables</h3><div id="ml307.s29"><h4>Identification of 7, 8, 9, 10-tetrahydro-6H-azepino[1,2-e]purine Scaffolds</h4><p>We initially tested 1210 compounds in dose response format and found:</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307tu2"><a href="/books/NBK143542/table/ml307.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml307tu2" rid-ob="figobml307tu2"><img class="small-thumb" src="/books/NBK143542/table/ml307.tu2/?report=thumb" src-large="/books/NBK143542/table/ml307.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml307.tu2"><a href="/books/NBK143542/table/ml307.tu2/?report=objectonly" target="object" rid-ob="figobml307tu2">Table</a></h4></div></div><div id="ml307.fu9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu9.jpg" alt="12." /></div><h3><span class="title">12</span></h3><div class="caption"><p>(CID 20912511) IC50 = 3.44 μM</p></div></div><p>Of the 72 members of the most potent scaffolds classes, several of the them contained chemical liabilities, i.e. Michael acceptor, frequent hitters, quinones, detergents, etc. and were eliminated from consideration. Compound <b>12</b> (CID 20912511) was identified as the most potent member of the 7, 8, 9, 10-tetrahydro-6H-azepino[1,2-e]purine scaffold in the initial hit series, although Compound <b>13</b> is almost as potent in our assay with an IC<sub>50</sub> = 3.87 μM. This scaffold does not contain any standard chemical liabilities.</p><p>Representative examples of other members of the initial screening hit set for this scaffold are compounds <b>2</b> to <b>23</b> in <a class="figpopup" href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object" rid-figpopup="figml307t4" rid-ob="figobml307t4">Table 4</a>.</p><p>After confirming the initial results, the hit-to-probe process was initiated both an analog by catalog approach and an internal medicinal chemistry effort. Using an analog by catalog approach, <b>37</b> additional analogs were purchased in the 7, 8, 9, 10-tetrahydro-6H-azepino[1,2-e]purine, 7- membered ring scaffolds <b>A</b> and <b>B</b>. It should be noted that few (if any) compounds with the 6- membered ring scaffolds are available commercially.</p><p>One of the purchased compounds entry <b>13</b>, CID 20912362 (<i>see</i>
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<a class="figpopup" href="/books/NBK143542/table/ml307.t5/?report=objectonly" target="object" rid-figpopup="figml307t5" rid-ob="figobml307t5">Table 5</a>: SAR Around Scaffolds A & B<b>),</b> is significantly more potent (IC<sub>50</sub> = 0.89 μM) than the original DPI plated compound. We synthesized entry <b>34</b>, in which the pendant amide of entry <b>13</b> was moved to the 4-position of the piperidine ring (Scaffold <b>B</b>) and activity of this molecule was significantly decreased, IC<sub>50</sub> = 40.1 μM.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t5"><a href="/books/NBK143542/table/ml307.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml307t5" rid-ob="figobml307t5"><img class="small-thumb" src="/books/NBK143542/table/ml307.t5/?report=thumb" src-large="/books/NBK143542/table/ml307.t5/?report=previmg" alt="Table 5. SAR Around Scaffolds A & B." /></a><div class="icnblk_cntnt"><h4 id="ml307.t5"><a href="/books/NBK143542/table/ml307.t5/?report=objectonly" target="object" rid-ob="figobml307t5">Table 5</a></h4><p class="float-caption no_bottom_margin">SAR Around Scaffolds <i>A</i> & <i>B</i>. </p></div></div><p>Looking closely at Scaffolds <b>A</b> and <b>B,</b> we examined analogs in which other groups replace the substituents on the phenyl ring. For example, when the chlorine atom of entry <b>13</b> is moved from the <i>meta</i> position to the para position on the aromatic ring, we observe a decrease in activity, entry <b>15</b>. Comparable decreases in activity are observed, if the chloride atom is replaced by a fluorine atom (entries <b>18</b> and <b>19</b>), a methyl group (entry <b>17</b>), and a di-methyl group (entry <b>23</b>). When we examine the lengthening of the carbon linker chain in entry <b>18</b> by 2 carbon atoms entry <b>16</b> the activities were similar. Another modification we made was replacing the piperidine ring of entry <b>19</b> (IC<sub>50</sub> = 9.91 μM) with a piperazine ring entry <b>31,</b> this modification resulted in the complete loss of activity, IC<sub>50</sub> > 100 μM.</p><p>Entry <b>13</b>, CID 20912362 has one chiral center on the piperidine ring. We synthesized both the <b>R</b> isomer entry <b>29,</b> IC<sub>50</sub> = 3.37 μM and the <b>S</b> isomer entry <b>30</b>, IC<sub>50</sub> = 15.0 μM. We were disappointed that the compounds were both less potent than the commercial racemic compound entry <b>13</b>.</p><p>Next, we investigated the effects of modifying the aryl amide substituents in Scaffold <b>B</b> and we found the most potent compound in this series of molecules was entry <b>35,</b> IC<sub>50</sub> = 3.73 μM. This compound contained a 3-chloro-4<b>-</b>methylphenyl ring. We observed small changes in substituents on the phenyl ring greatly altered the activity. For example, when the 2-chlor-3-methylphenyl ring was substituted, entry <b>42</b>, the compound was completely inactive, IC<sub>50</sub> > 100 μM. Any subsequent changes to the original combination of atoms on the phenyl ring resulted in the decrease in activity of the series. (See entries <b>35 – 47, 57</b>). In addition we observed that replacement of the phenyl ring with a benzyl, substituted benzyl or phenyethyl moieties (See entries <b>48 – 55</b>). resulted in compounds that are less potent than entry <b>34</b>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t6"><a href="/books/NBK143542/table/ml307.t6/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml307t6" rid-ob="figobml307t6"><img class="small-thumb" src="/books/NBK143542/table/ml307.t6/?report=thumb" src-large="/books/NBK143542/table/ml307.t6/?report=previmg" alt="Table 6. SAR Around Scaffold B." /></a><div class="icnblk_cntnt"><h4 id="ml307.t6"><a href="/books/NBK143542/table/ml307.t6/?report=objectonly" target="object" rid-ob="figobml307t6">Table 6</a></h4><p class="float-caption no_bottom_margin">SAR Around Scaffold <i>B</i>. </p></div></div><p>Finally, we investigated the effects of the changing the 7-membered ring scaffolds <b>A</b> and <b>B</b>, to 6-membered ring scaffolds <b>C, D, E</b> and <b>F.</b> To this end, a select group of nineteen (<b>19</b>) analogs were synthesized and the results are presented in <a class="figpopup" href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object" rid-figpopup="figml307t4" rid-ob="figobml307t4">Table 4C</a>. A comparison of the activities shows that Scaffolds <b>C</b> and <b>D</b> when compared to their counterparts in Scaffolds <b>A</b> and <b>B,</b> all compounds displayed similar activity. For example entry <b>58</b> (Scaffold <b>B)</b> has an IC<sub>50</sub> = 23.8 μM and when compared to its counterpart entry <b>68 (</b>Scaffold <b>D</b>) IC<sub>50</sub> = 27.2 μM.</p><p>The most interesting compound in the series of synthesized molecules is entry <b>60</b> (CID 56593285, IC <sub>50</sub> = 0.962 μM).</p><div id="ml307.fu10" class="figure"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu57.jpg" alt="Image ml307fu57" /></div></div><p>The comparable compound in which the chlorine atom is moved to the <i>ortho</i> position entry <b>59</b> (CID 56593287<i>)</i> has similar activity IC <sub>50</sub> = 1.04 μM. Moving the chlorine atom to the para position entry 61 (CID 56593276) results in a decrease in activity, IC <sub>50</sub> = 6.79 μM. Replacing the chlorine atom with methyl, di-chloro, dimethyl, fluoro, etc. atoms results in a decrease in activity. In Scaffold <b>E</b>, entry <b>60 (</b>CID 56593285, IC <sub>50</sub> = 0.962 μM) when the meta-chlorphenyl substituent is attached to Scaffold <b>F,</b> entry <b>69</b>, the activity of the molecule greatly diminishes, IC <sub>50</sub> = 12.6 μM. Generally, Scaffold <b>C and E</b> are preferred over Scaffold <b>D and F.</b></p><p>From these results we focused on Entry <b>60</b>, which has one chiral center. We thought it would be interesting to synthesize both the <b>R</b> and <b>S</b> isomers of this molecule. To this end we synthesized the <b>R</b>-isomer entry <b>70</b> (CID 56639556, IC <sub>50</sub> = 0.781 μM ) and the S-isomer entry 71 (CID 56639543, IC<sub>50</sub> = 2.66 μM<b>).</b> For the probe molecule we identified entry <b>70</b>, <b>CID 56639556 (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134958980</a></b>) as our most potent molecule screened in both the purchased and synthesized molecular set. However this 3-fold improvement in potency indicates that there isn’t a very strong stereochemical dependence for inhibition.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml307t7"><a href="/books/NBK143542/table/ml307.t7/?report=objectonly" target="object" title="Table 7" class="img_link icnblk_img figpopup" rid-figpopup="figml307t7" rid-ob="figobml307t7"><img class="small-thumb" src="/books/NBK143542/table/ml307.t7/?report=thumb" src-large="/books/NBK143542/table/ml307.t7/?report=previmg" alt="Table 7. SAR Around Scaffolds C, D, E and F." /></a><div class="icnblk_cntnt"><h4 id="ml307.t7"><a href="/books/NBK143542/table/ml307.t7/?report=objectonly" target="object" rid-ob="figobml307t7">Table 7</a></h4><p class="float-caption no_bottom_margin">SAR Around Scaffolds <i>C</i>, <i>D</i>, <i>E</i> and <i>F</i>. </p></div></div></div></div><div id="ml307.s30"><h3>3.5. Cellular Activity</h3><p>Cytotoxicity assays in immortalized human cell lines will be used to assess LD<sub>50</sub>. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> will be tested for inhibition of known Ubc13 ubiquitination targets. One approach will be to transiently transfect TRAF6, a known target of Ubc13, and monitor the ubiquitination level of this assay with Western blot analysis. To determine the selectivity of <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> for inhibition of K-63 specific ubiquitination and therefore Ubc13 specificity a cell based p53 ubiquitination assay will be performed. The ubquitination of p53 is a K-48 mediated event, which is mediated by other E2s (not Ubc13) and therefore should not be affected by <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a>.</p></div><div id="ml307.s31"><h3>3.6. Profiling Assays</h3><p>As a <i>pro forma</i> activity, the SBCCG is committed to profiling all final probe(s) compound(s) and in certain cases key informative analogs in the PanLabs full panel as negotiated by the MLPCN network. Additional commercial profiling services will be considered for funding by SBCCG as deemed appropriate and informative.</p><p>The nominated probe was evaluated in a detailed <b><i>in vitro</i></b> pharmacology screen as shown in <a class="figpopup" href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object" rid-figpopup="figml307t8" rid-ob="figobml307t8">Table 8</a>:</p><p><a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is very soluble in aqueous media at pH 5.0/6.2/7.4. With solubilities in pION buffer of 348 μM (pH5.0), 351 μM (pH6.2), and 373 μM (pH7.4), which are 446-fold, 449-fold, and 478-fold its <b><i>in vitro</i></b> potency of 781 nM. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is also comparably soluble in 1X PBS (pH 7.4) with a solubility of 352 μM, which is 451-fold its potency (IC50 value).</p><p>The <b>PAMPA</b> (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <b><i>in vitro</i></b> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. Consistent with the predicted LogP (see <a class="figpopup" href="/books/NBK143542/table/ml307.t3/?report=objectonly" target="object" rid-figpopup="figml307t3" rid-ob="figobml307t3">Table 3</a>), <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is moderately permeable at pH5.0 and very permeable at pH 6.2 and 7.4 in this assay.</p><p><b>Plasma Protein Binding</b> is a measure of a drug’s efficiency to bind to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> shows high binding to plasma proteins in both mouse and human plasma.</p><p><b>Stability in PBS and in 1:1 PBS Acetonitrile.</b> As <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is very soluble in PBS, stability measurement are not confounded by compound solubility issues, and <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is apparently fairly stable in PBS and completely stable in 1:1 PBS:Acetonitrile with 80.51% and 100% of parent <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> remaining after 48 hr of incubation at ambient temperature.</p><p><b>Plasma Stability</b> is a measure of the stability of small molecules and peptides in plasma and is an important parameter, which strongly can influence the <b><i>in vivo</i></b> efficacy of a test compound. Drug candidates are exposed in plasma to enzymatic processes (proteinases, esterases), and they can undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> shows excellent stability in human and mouse plasma.</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. This assay addresses the pharmacologic question of how long the parent compound will remain circulating in plasma within the body. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> shows poor stability in both human and mouse liver homogenates, potentially limiting the utility of this probe in <b><i>in vivo</i></b> rodent models and in a human therapeutic context. This is one area of needed improvement for future PK optimization approaches. However, it will still be a useful <i>in vitro</i> tool for probing the chemical biology and biochemical mechanism of inhibition, as these are not subject to “first-pass” liver metabolism.</p><p><a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> exhibits no toxicity (LC<sub>50</sub> > 50 μM) toward human hepatocyctes.</p></div></div><div id="ml307.s32"><h2 id="_ml307_s32_">4. Discussion</h2><p>Here we report a novel small molecule inhibitor of Ubc13-dependent poly-ubiquitination. This was achieved with the successful collaboration between the Sanford-Burnham Center for Chemical Genomics, and the research laboratory of the assay provider (Dr. John C. Reed). Following significant chemical optimization, we identified <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> as a potent, sub-μM, inhibitor of the E2 ubquitination enzyme, Ubc13. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> offers exciting opportunities as a tool compound to further elucidate the specific role K63-dependent ubiquitination plays in cellular biology.</p><div id="ml307.s33"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>Previously the most potent inhibitor of Ubc13 was isolated from the marine sponge <i>Leucetta Microrhaphis</i> This non-drug-like compound was identified as leucettamol A (<b>1</b>). with an estimated IC<sub>50</sub> value of 50 μg/mL (~110 μM; m.w. 472). This compound is not very stable and isomerizes readily. Hydrogenation of compound <b>1</b> produced compound <b>3</b>, with a potency of ~ 4 μg/mL (~<b>8</b> μM),</p><div id="ml307.fu11" class="figure"><div class="graphic"><img src="/books/NBK143542/bin/ml307fu71.jpg" alt="Image ml307fu71" /></div></div><p>The patent literature (WO2008/009758), describes compounds that effect UBC13-UEV interactions. The patent gives no definitive data on the claimed compounds. We synthesized the compounds but were unable to confirm its activity against Ubc13 using the TR-FRET biochemical assay.</p><p>In this report we have identified the most potent Ubc13 inhibitor, in the literature to date, <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> (CID 56639556) IC <sub>50</sub> = 0.781 μM. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> is >10-fold more potent than any known compound in the literature and it is chemically stable and will serve as a unique biochemical probe. This probe will be useful for specifically modulating Ubc13-dependent cellular functions. Indeed, Ubc13 currently performs such novel functions by the formation of differential holoenzymes containing Uev1A or mms2 affecting inflammation and DNA damage repair, respectively; the latter of which holds major implications for cancer intervention. <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> will be very useful to researchers exploring immunomodulation and inflammation as well as those in the fields of cancer biology. Finally, the larger research community who study UBC13 and ubiquitination-regulated pathways will certainly be beneficiaries of such inhibitors.</p></div><div id="ml307.s34"><h3>4.2. Mechanism of Action Studies</h3><p>Analogs were also profiled for their ability to suppress TRAF6 ubquitination in HEK293T cells, showing inhibition by active compounds but not compounds that fail to show activity in the biochemical TR-FRET assay. Additionally, analogs of <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> were identified that failed to suppress K48-linked ubquitination of p53 mediated by the E3 ligase Mdm2, which partners with other E2 enzymes in phenotypic or cell signaling pathway based assays. Planned future studies will determine mechanism of action or provide a plan to biochemically identify and characterize the mechanisms of action.</p></div><div id="ml307.s35"><h3>4.3. Planned Future Studies</h3><p>The Assay Provider’s future plans for characterization of the probe compound focus on elaborating its biochemical mechanism and on characterizing its cellular activity. For biochemical mechanism, it will be determined whether the compound interferes with cofactor (UEV1a, MMS2) binding to Ubc13. Additional, the approximate binding site of the compound will be mapped by 2D-NMR experiments using 1H-15N-Ubc13. It is possible that the probe compound binds cofactor UEV1a instead of Ubc13, which will be determined by comparing the affinity of the compound for Ubc13 versus UEV1a by isothermal titration calorimetry (ITC) and NMR experiments. For cellular activity, the probe compound will be profiled using the same TRAF6 and p53 ubiquitination assays used for analog compounds. Additionally, cell-based assays for other categories of E2 enzymes are in production, including SUMOylation (Ubc9) and NEDDylation (Ubc12). Inhibitory activity against various Ubc13-mediated signal transduction pathways will also be assessed, including NF-κB and stress kinase activation induced by cytokines, TLR ligands, PKC-activators and DNA-damaging agents. Lastly, it would be advantageous to embark on a SAR campaign oriented to improving microsomal stability.</p></div></div><div id="ml307.s36"><h2 id="_ml307_s36_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml307.r1">Chen ZJ. <span><span class="ref-journal">Nat Cell Biol. </span>2005;<span class="ref-vol">7</span>:758–765.</span> [<a href="/pmc/articles/PMC1551980/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1551980</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16056267" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16056267</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml307.r2">Cao Z, Xiong J, Takeuchi M, Kurama T, Goeddel DV. <span><span class="ref-journal">Nature. </span>1996;<span class="ref-vol">383</span>:443–446.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8837778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 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[<a href="/pmc/articles/PMC524439/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC524439</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15492226" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15492226</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml307.r18">Shi CS, Kehrl JH. <span><span class="ref-journal">J Biol Chem. </span>2003;<span class="ref-vol">278</span>(17):15429–15434.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12591926" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12591926</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml307.r19">Wang C, Deng L, Hong M, Akkaraju GR, Inoue J-I, Chen ZJ. <span><span class="ref-journal">Nature. </span>2001;<span class="ref-vol">412</span>:346–351.</span> [<a 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id="ml307.r24">VanDemark AP, Hofmann RM, Tsui C, Pickart CM, Wolberger C. <span><span class="ref-journal">Cell. </span>2001;<span class="ref-vol">105</span>:711–720.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11440714" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11440714</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml307.r25">Zhang M, Windheim M, Roe SM, Peggie M, Cohen P, Prodromou C, Pearl LH. <span><span class="ref-journal">Mol Cell. </span>2005;<span class="ref-vol">20</span>:525–538.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16307917" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16307917</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml307.r26">Andersen PL, Zhou H, Pastushok L, Moraes T, McKenna S, Ziola B, Ellison MJ, Dixit VM, Xiao W. <span><span 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class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml307.r28">Fukushima T, Matsuzawa S, Kress CL, Bruey JM, Krajewska M, Lefebvre S, Zapata JM, Ronai Z, Reed JC. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2007;<span class="ref-vol">104</span>(15):6371–6376.</span> [<a href="/pmc/articles/PMC1851032/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1851032</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17404240" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17404240</span></a>]</div></dd></dl></dl></div><div id="ml307.s37"><h2 id="_ml307_s37_">6. Supplementary Information</h2><div id="ml307.s38"><h3>6.1. Assay Details</h3><div id="ml307.s39"><h4>Primary Assay and Secondary Assay Protocol</h4><div id="ml307.s40"><h5>Materials</h5><ul><li class="half_rhythm"><div>Assay buffer: 50 mM Hepes (pH 7.5), 0.1mM DTT, 0.005% Empigen, 0.1% BSA, 1.25 mM MgCl2</div></li><li class="half_rhythm"><div>E1: Produced at the Sanford-Burnham Medical Research Institute’s protein production core facility</div></li><li class="half_rhythm"><div>Fl-Ub: Invitrogen</div></li><li class="half_rhythm"><div>Tb-Ub: Invitrogen</div></li><li class="half_rhythm"><div>ATP: Sigma</div></li><li class="half_rhythm"><div>Ubc13: Produced at the Sanford-Burnham Medical Research Institute’s protein production core facility</div></li><li class="half_rhythm"><div>Uev1a: Produced at the Sanford-Burnham Medical Research Institute’s protein production core facility</div></li><li class="half_rhythm"><div>Assay plate: Corning 1536 Well White Plate (Catalogue #: 3725)</div></li></ul></div><div id="ml307.s41"><h5>Protocol</h5><div id="ml307.s42"><h5>I. Compound Addition</h5><ol><li class="half_rhythm"><div class="half_rhythm">Using LabCyte Echo, transfer 40 nL from a 2 mM Echo qualified plate containing test compounds into assay plate columns 5 – 48 (final concentration of test compounds is 20 microM, 1.0 % DMSO). Transfer 40 nL of DMSO to positive and negative control wells in columns 1 – 4.</div></li><li class="half_rhythm"><div class="half_rhythm">Centrifuge plates at 1000 rpm for 1 min.</div></li><li class="half_rhythm"><div class="half_rhythm">Seal the plates and leave them at RT.</div><div class="half_rhythm">Note: Compounds are added to the plates before reagent addition</div></li></ol></div><div id="ml307.s43"><h5>II. Set up of Ubc13 assay</h5><p>Prepare assay buffer</p><ol class="lower-alpha"><li class="half_rhythm"><div>E2: E2 is prepared in two steps. First, prepare E2 stock from Ubc13 and Uev1a at 10 μM. This E2 stock will form a heterodimer after 2 hour incubation at 4 degrees C. After 2 hour incubation at 4 degrees C, dilute E2 stock in assay buffer to make 2 X intermediate solution at 250 nM.</div></li><li class="half_rhythm"><div>E1/Ub/ATP: 30 minutes before the end of E2 stock incubation at 4 degrees C, prepare 2X intermediate E1/Ub/ATP solution with E1 at 200 nM, Fl-Ub at 150 nM, Tb-Ub at 12 nM, and ATP at 2 mM.</div></li></ol></div><div id="ml307.s44"><h5>III. Reagent Addition</h5><ol><li class="half_rhythm"><div>Add 2 μL assay buffer to columns 1&2</div></li><li class="half_rhythm"><div>Add 2 μL 2X intermediate E2 to columns 3 – 48</div></li><li class="half_rhythm"><div>Add 2 μL 2X intermediate E1/Ub/ATP to all columns</div></li><li class="half_rhythm"><div>Incubate at RT for 90 mins</div></li></ol></div><div id="ml307.s45"><h5>IV. Reading plates</h5><ol><li class="half_rhythm"><div>After 90 minutes of incubation, plates are read</div></li><li class="half_rhythm"><div>Read plates using BMG PHERAstar FS using Lanthascreen protocol.</div></li></ol></div></div></div><div id="ml307.s46"><h4>Secondary Bfl-1 Assay: Dry Powder Protocol</h4><div id="ml307.s47"><h5>Materials</h5><ul><li class="half_rhythm"><div>Assay buffer: 25 mM Bis-Tris, 1mM TCEP, 0.005% Tween 20</div></li><li class="half_rhythm"><div>Bfl-1: Produced at the Sanford-Burnham Medical Research Institute</div></li><li class="half_rhythm"><div>F-Bid: Produced at the Sanford-Burnham Medical Research Institute</div></li><li class="half_rhythm"><div>Tb × GST: Invitrogen (Catalogue #: PV3551)</div></li><li class="half_rhythm"><div>TCEP: Sigma (Catalogue #: 646547)</div></li><li class="half_rhythm"><div>Assay plate: Corning 1536 Well White Plate (Catalogue #: 3725)</div></li></ul></div><div id="ml307.s48"><h5>Protocol</h5><div id="ml307.s49"><h5>I. Compound Addition</h5><ol><li class="half_rhythm"><div class="half_rhythm">Using LabCyte Echo, transfer 40 nL from a 10 mM Echo qualified plate containing test compounds into assay plate columns 5 – 48 (final concentration of test compounds is 100 microM, 1.0 % DMSO). Transfer 40 nL of DMSO to positive and negative control wells in columns 1 – 4.</div></li><li class="half_rhythm"><div class="half_rhythm">Centrifuge plates at 1000 rpm for 1 min.</div></li><li class="half_rhythm"><div class="half_rhythm">Seal the plates and leave them at RT.</div><div class="half_rhythm">Note: Compounds are added to the plates before reagent addition</div></li></ol></div><div id="ml307.s50"><h5>II. Set up of Bfl-1 assay</h5><ol><li class="half_rhythm"><div>Prepare assay buffer</div></li><li class="half_rhythm"><div>Bfl-1: Dilute Bfl-1 in assay buffer to make 2X intermediate solution at 10 nM</div></li><li class="half_rhythm"><div>F-Bib/Tb × GST: Dilute F-Bid and Tb × GST in assay buffer to make 2X intermediate solution at the concentration of 8 nM for F-Bid and 5 nM for Tb × GST.</div></li></ol></div><div id="ml307.s51"><h5>III. Reagent Addition</h5><ol><li class="half_rhythm"><div>Add 2 μL assay buffer to columns 1&2</div></li><li class="half_rhythm"><div>Add 2 μL 2X intermediate Bfl-1 to columns 3 – 48</div></li><li class="half_rhythm"><div>Add 2 μL of 2X intermediate F-Bid/Tb × GST to all columns</div></li></ol></div><div id="ml307.s52"><h5>IV. Reading plates</h5><ol><li class="half_rhythm"><div>10. Read plates using BMG PHERAstar FS using Lanthascreen protocol.”</div></li></ol></div></div></div><div id="ml307.s53"><h4>Secondary Caspase-3 Assay: Dry Powder Protocol</h4><div id="ml307.s54"><h5>Materials</h5><ul><li class="half_rhythm"><div>Caspase-Glo® - 3/7 Assay: Promega (Catalogue #: G8092)</div></li><li class="half_rhythm"><div>Assay buffer: 150 mM Hepes (pH 7.8), 4.0 mM DTT, 1.0 mM EDTA, 0.01% Tween, 0.1% BSA</div></li><li class="half_rhythm"><div>Assay plate: Corning 1536 Well White Plate (Catalogue #: 3725)</div></li></ul></div><div id="ml307.s55"><h5>Protocol</h5><div id="ml307.s56"><h5>I. Compound Addition</h5><ol><li class="half_rhythm"><div>Using LabCyte Echo, transfer 20 nL from a 10 mM Echo qualified plate containing test compounds into assay plate columns 5 – 48 (final concentration of test compounds is 100 microM, 1.0 % DMSO). Transfer 20 nL of DMSO to positive and negative control wells in columns 1 – 4.</div></li><li class="half_rhythm"><div>Centrifuge plates at 1000 rpm for 1 min.</div></li><li class="half_rhythm"><div>Seal the plates and leave them at RT.</div></li></ol><p>Note: Compounds are added to the plates before reagent addition</p></div><div id="ml307.s57"><h5>II. Set up of Caspase-3 assay</h5><ol><li class="half_rhythm"><div>Prepare assay buffer</div></li><li class="half_rhythm"><div>Caspase 3: Dilute Caspase 3 in assay buffer to make 2X intermediate solution at 0.046 nM</div></li><li class="half_rhythm"><div>Caspase Glo substrate: Dilute 1X substrate solution in assay buffer to make 2X intermediate solution at 0.75X</div></li></ol></div><div id="ml307.s58"><h5>III. Reagent Addition</h5><ol><li class="half_rhythm"><div>Add 1 μL assay buffer to columns 1 & 2</div></li><li class="half_rhythm"><div>Add 1 μL 2X intermediate Caspase 3 to columns 3 – 48</div></li><li class="half_rhythm"><div>Add 1 μL 2X intermediate Caspase Glo substrate to all columns</div></li><li class="half_rhythm"><div>Incubate at RT for 60 mins</div></li></ol></div><div id="ml307.s59"><h5>IV. Reading plates</h5><ol><li class="half_rhythm"><div>Read plates using PerkinElmer ViewLux using SENP Luminescence 60 sec protocol.</div></li></ol></div></div></div></div><div id="ml307.s60"><h3>6.2. <sup>1</sup>H NMR and LC-MS spectra of ML307</h3><div id="ml307.fu12" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=1H%20NMR%20Spectrum%20of%20ML307%20(500%20MHz%2C%20CDCl3).&p=BOOKS&id=143542_ml307fu72.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK143542/bin/ml307fu72.jpg" alt="1H NMR Spectrum of ML307 (500 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title"><sup>1</sup>H NMR Spectrum of ML307 (500 MHz, CDCl<sub>3</sub>)</span></h3></div><div id="ml307.fu13" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=LC-MS%20for%20ML307.&p=BOOKS&id=143542_ml307fu73.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK143542/bin/ml307fu73.jpg" alt="LC-MS for ML307." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">LC-MS for ML307</span></h3><div class="caption"><p>(Reverse phase C18 column: isocratic)</p></div></div></div></div><div style="display:none"><div style="display:none" id="figml307f6"><img alt="Image ml307f6" src-large="/books/NBK143542/bin/ml307f6.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK143542_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Robert Ardecky</span>,<sup>1</sup> <span itemprop="author">Charitha Madiraju</span>, <span itemprop="author">Shu-ichi Matsuzawa</span>, <span itemprop="author">Jiwen Zou</span>,<sup>1</sup> <span itemprop="author">Santhi Ganji</span>,<sup>1</sup> <span itemprop="author">Ian Pass</span>,<sup>1</sup> <span itemprop="author">Tram A. Ngo</span>,<sup>1</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>1</sup> <span itemprop="author">Eduard Sergienko</span>,<sup>1</sup> <span itemprop="author">Ying Su</span>,<sup>1</sup> <span itemprop="author">Derek Stonich</span>,<sup>1</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>2</sup> <span itemprop="author">Michael Vicchiarelli</span>,<sup>2</sup> <span itemprop="author">Danielle McAnally</span>,<sup>2</sup> <span itemprop="author">Layton H. Smith</span>,<sup>2</sup> <span itemprop="author">Jena Diwan</span>,<sup>1</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>1</sup> <span itemprop="author">Yasuko Matsuzawa</span>, <span itemprop="author">Carina Wimer</span>, <span itemprop="author">Paul W. Diaz</span>,<sup>3</sup> and <span itemprop="author">John C. Reed</span><sup>3</sup>.<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup></p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.</div><div class="affiliation"><sup>2</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida 32827, USA.</div><div class="affiliation"><sup>3</sup>
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Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding Author: Thomas D. Y. Chung. Email:
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<a href="mailto:dev@null" data-email="gro.mahnrubdrofnas@gnuhct" class="oemail">gro.mahnrubdrofnas@gnuhct</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 16, 2012</span>; Last Update: <span itemprop="dateModified">May 13, 2014</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Ardecky R, Madiraju C, Matsuzawa S, et al. Selective UBC 13 Inhibitors. 2012 Apr 16 [Updated 2014 May 13]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml308/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml306/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml307fu1"><div id="ml307.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu1.jpg" alt="ML307." /></div><h3><span class="title">ML307</span></h3></div></article><article data-type="table-wrap" id="figobml307tu1"><div id="ml307.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml307.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml307.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml307.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml307.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml307.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml307.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fold Selective</th><th id="hd_h_ml307.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml307.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 56639556<br />CID <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a></td><td headers="hd_h_ml307.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">UBC13</td><td headers="hd_h_ml307.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">781 ± 10 (n=2)<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134958980</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602404" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602404</a>]</td><td headers="hd_h_ml307.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Caspase 3<br /><br />SH- Protease Counter-screen</td><td headers="hd_h_ml307.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>100,000 (n=2) [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134958980</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602401</a>]</td><td headers="hd_h_ml307.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>128 X</td><td headers="hd_h_ml307.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Bfl-1: IC<sub>50</sub>>100,000 (n=2)<br />TR-FRET artifact[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134958980</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602400" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602400</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml307f1"><div id="ml307.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307f1.jpg" alt="UBC13 Prior Art" /></div><h3><span class="label">Figure 1</span><span class="title">Natural Product Prior Art compounds</span></h3><div class="caption"><p>Compound (1) is registered in PubChem – See SIDs therein</p></div></div></article><article data-type="fig" id="figobml307f2"><div id="ml307.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307f2.jpg" alt="UBC13 Prior Art 2" /></div><h3><span class="label">Figure 2</span><span class="title">Prior Art compounds described in Patent for UBC13/UEV</span></h3><div class="caption"><p>PubChem CID for the described compounds are noted</p></div></div></article><article data-type="table-wrap" id="figobml307t1"><div id="ml307.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Summary of Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChemBioAssay Name</th><th id="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary of small molecule inhibitors of UBC13 Polyubiquitin</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485343" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">485343</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">uHTS identification of UBC13 Polyubiquitin Inhibitors via a TR-FRET Assay</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485273" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">485273</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Single concentration confirmation of uHTS for the identification of UBC13 Polyubiquitin Inhibitors via a TR-FRET Assay(Cherry Pick)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488859" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488859</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Dose Response confirmation of uHTS for the identification of UBC13 Polyubiquitin Inhibitors via a TR-FRET Assay (DMSO Dose Response)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493155" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493155</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493182" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493182</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR analysis of small molecule UBC13 Polyubiquitin Inhibitors via a TR-FRET Assay (Dry Powder)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504687" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504687</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588390" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588390</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602205" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602205</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602404" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602404</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Dose Response confirmation of UBC13 Polyubiquitin Inhibitors using a Bfl-1 counterscreen (DMSO Dose Response)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504689" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504689</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR Analysis of small molecule UBC13 Polyubiquitin Inhibitors using a Bfl-1 counterscreen (Dry Powder)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504685" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504685</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588376" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588376</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602206" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602206</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602400" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602400</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Single concentration confirmation of UBC13 Polyubiquitin Inhibitors using a Caspase-3 counter screen (Cherry Pick)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488856" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">488856</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr><tr><td headers="hd_h_ml307.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SAR Analysis of small molecule UBC13 Polyubiquitin Inhibitors using a Caspase-3 counterscreen (Dry Powder)</td><td headers="hd_h_ml307.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504680" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504680</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588375" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588375</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602207" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602207</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602401" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602401</a></td><td headers="hd_h_ml307.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml307.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity</td><td headers="hd_h_ml307.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml307.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fluorescence & 1536 well</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml307f3"><div id="ml307.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307f3.jpg" alt="Figure 3. Structure of ML307." /></div><h3><span class="label">Figure 3</span><span class="title">Structure of ML307</span></h3><div class="caption"><p>Note R-configuration stereochemistry as indicated around the 3-position of the piperdine ring.</p></div></div></article><article data-type="fig" id="figobml307f6"><div id="ml307.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%201.%20Synthesis%20of%20ML307%2C%20conditions.&p=BOOKS&id=143542_ml307f6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK143542/bin/ml307f6.jpg" alt="Scheme 1. Synthesis of ML307, conditions." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML307, conditions</span></h3><div class="caption"><p><b>a</b>. DMF, 113 °C, overnight (46%); <b>b</b>. Triethylorthoformate, DMF, 150 °C, overnight (58%); <b>c</b>. POCl<sub>3,</sub> CH<sub>3</sub>CN, 90 °C (59%); <b>d</b>. DIPEA, DCM, rt, overnight; <b>e</b>.4M HCl, Dioxane (60%, 2 steps); <b>f</b>. EDCI, HOBT, DIPEA, DMF, rt, overnight (53%); <b>g</b>. 10% TFA, DCM (100%); <b>h</b>. K<sub>2</sub>CO<sub>3,</sub> CH<sub>3</sub>CN, 80 °C (54%).</p></div></div></article><article data-type="fig" id="figobml307f4"><div id="ml307.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307f4.jpg" alt="Figure 4. Stability of ML307 in (△) PBS or (●) 1:1 acetonitrile:PBS at room temperature." /></div><h3><span class="label">Figure 4</span><span class="title">Stability of ML307 in (△) PBS or (●) 1:1 acetonitrile:PBS at room temperature</span></h3></div></article><article data-type="table-wrap" id="figobml307t2"><div id="ml307.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Hydrolytic stability of <b>ML307</b> at ambient temperature</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml307.t2_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml307.t2_1_1_1_1" style="text-align:center;vertical-align:middle;">Time (hr)</th><th id="hd_h_ml307.t2_1_1_1_2" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">% Remaining by LC/MS</th></tr><tr><th headers="hd_h_ml307.t2_1_1_1_2" id="hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PBS</th><th headers="hd_h_ml307.t2_1_1_1_2" id="hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1:1 ACN:PBS</th></tr></thead><tbody><tr><td headers="hd_h_ml307.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.00</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.00</td></tr><tr><td headers="hd_h_ml307.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">93.15</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">94.03</td></tr><tr><td headers="hd_h_ml307.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">83.02</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.00</td></tr><tr><td headers="hd_h_ml307.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">87.43</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.00</td></tr><tr><td headers="hd_h_ml307.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">73.99</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.00</td></tr><tr><td headers="hd_h_ml307.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">80.51</td><td headers="hd_h_ml307.t2_1_1_1_2 hd_h_ml307.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100.00</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml307t3"><div id="ml307.t3" class="table"><h3><span class="label">Table 3</span><span class="title">CID 56639556 [ML307] MLS-0471611</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t3_lrgtbl__"><table class="no_top_margin"><tbody><tr><th id="hd_b_ml307.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Weight [g/mol]</th><td headers="hd_b_ml307.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">568.11012</td></tr><tr><th id="hd_b_ml307.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Molecular Formula</th><td headers="hd_b_ml307.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">C<sub>29</sub>H<sub>38</sub>ClN<sub>7</sub>O<sub>3</sub></td></tr><tr><th id="hd_b_ml307.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AlogP</th><td headers="hd_b_ml307.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.079</td></tr><tr><th id="hd_b_ml307.t3_1_1_4_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Donor</th><td headers="hd_b_ml307.t3_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr><tr><th id="hd_b_ml307.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">H-Bond Acceptor</th><td headers="hd_b_ml307.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td></tr><tr><th id="hd_b_ml307.t3_1_1_6_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rotatable Bond Count</th><td headers="hd_b_ml307.t3_1_1_6_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td></tr><tr><th id="hd_b_ml307.t3_1_1_7_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Exact Mass</th><td headers="hd_b_ml307.t3_1_1_7_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">567.272466</td></tr><tr><th id="hd_b_ml307.t3_1_1_8_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MonoIsotopic Mass</th><td headers="hd_b_ml307.t3_1_1_8_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">567.272466</td></tr><tr><th id="hd_b_ml307.t3_1_1_9_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Topological Polar Surface Area</th><td headers="hd_b_ml307.t3_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">117</td></tr><tr><th id="hd_b_ml307.t3_1_1_10_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Heavy Atom Count</th><td headers="hd_b_ml307.t3_1_1_10_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">40</td></tr><tr><th id="hd_b_ml307.t3_1_1_11_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Formal Charge</th><td headers="hd_b_ml307.t3_1_1_11_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><th id="hd_b_ml307.t3_1_1_12_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Complexity</th><td headers="hd_b_ml307.t3_1_1_12_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">775</td></tr><tr><th id="hd_b_ml307.t3_1_1_13_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Isotope Atom Count</th><td headers="hd_b_ml307.t3_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><th id="hd_b_ml307.t3_1_1_14_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Atom StereoCenter Count</th><td headers="hd_b_ml307.t3_1_1_14_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><th id="hd_b_ml307.t3_1_1_15_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Atom StereoCenter Count</th><td headers="hd_b_ml307.t3_1_1_15_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><th id="hd_b_ml307.t3_1_1_16_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Defined Bond StereoCenter Count</th><td headers="hd_b_ml307.t3_1_1_16_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><th id="hd_b_ml307.t3_1_1_17_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Undefined Bond StereoCenter Count</th><td headers="hd_b_ml307.t3_1_1_17_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><th id="hd_b_ml307.t3_1_1_18_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Covalently-Bonded Unit Count</th><td headers="hd_b_ml307.t3_1_1_18_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml307t4"><div id="ml307.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Probe and Analog Submissions to MLSMR (BioFocus DPI) for UBC13 Inhibitors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml307.t4_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a> - CID56639556</th></tr><tr><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (BCCG)</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or syn)</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml307.t4_1_1_1_1" id="hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Date ordered/submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML307[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML307</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471611</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004256644</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639556</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958980" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958980</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Syn</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">31.8</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3/31/2012</td></tr><tr><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471622</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004256643</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912564</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958967" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958967</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Syn</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26.2</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3/31/2012</td></tr><tr><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471621</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004256642</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832464</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958966" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958966</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Syn</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23.7</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3/31/2012</td></tr><tr><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471627</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004256641</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832476</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958972" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958972</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Syn</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">21.3</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3/31/2012</td></tr><tr><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471620</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004256640</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832461</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958964" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958964</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Syn</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24.6</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3/31/2012</td></tr><tr><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469614</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004256639</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912547</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958963" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958963</a></td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Syn</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.1</td><td headers="hd_h_ml307.t4_1_1_1_1 hd_h_ml307.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3/31/2012</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml307fu2"><div id="ml307.fu2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu2.jpg" alt="3." /></div><h3><span class="title">3</span></h3></div></article><article data-type="fig" id="figobml307fu3"><div id="ml307.fu3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu3.jpg" alt="4." /></div><h3><span class="title">4</span></h3></div></article><article data-type="fig" id="figobml307fu4"><div id="ml307.fu4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu4.jpg" alt="5." /></div><h3><span class="title">5</span></h3></div></article><article data-type="fig" id="figobml307fu5"><div id="ml307.fu5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu5.jpg" alt="8." /></div><h3><span class="title">8</span></h3></div></article><article data-type="fig" id="figobml307fu6"><div id="ml307.fu6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu6.jpg" alt="10." /></div><h3><span class="title">10</span></h3></div></article><article data-type="fig" id="figobml307fu7"><div id="ml307.fu7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu7.jpg" alt="11." /></div><h3><span class="title">11</span></h3></div></article><article data-type="fig" id="figobml307f5"><div id="ml307.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307f5.jpg" alt="Figure 5. Screening results and Hit validation." /></div><h3><span class="label">Figure 5</span><span class="title">Screening results and Hit validation</span></h3></div></article><article data-type="fig" id="figobml307fu8"><div id="ml307.fu8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu8.jpg" alt="Representative Dose Response of ML307 in the Ubc13 TR-FRET, Caspase-3 and Bfl-1 Assays." /></div><h3><span class="title">Representative Dose Response of ML307 in the Ubc13 TR-FRET, Caspase-3 and Bfl-1 Assays</span></h3></div></article><article data-type="table-wrap" id="figobml307tu2"><div id="ml307.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml307.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Number of compounds</th><th id="hd_h_ml307.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Potency thresholds (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml307.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">72</td><td headers="hd_h_ml307.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">< 5</td></tr><tr><td headers="hd_h_ml307.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">87</td><td headers="hd_h_ml307.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">< 10</td></tr><tr><td headers="hd_h_ml307.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">194</td><td headers="hd_h_ml307.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">< 20</td></tr><tr><td headers="hd_h_ml307.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">857</td><td headers="hd_h_ml307.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 20</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml307fu9"><div id="ml307.fu9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu9.jpg" alt="12." /></div><h3><span class="title">12</span></h3><div class="caption"><p>(CID 20912511) IC50 = 3.44 μM</p></div></div></article><article data-type="table-wrap" id="figobml307t5"><div id="ml307.t5" class="table"><h3><span class="label">Table 5</span><span class="title">SAR Around Scaffolds <b>A</b> & <b>B</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml307.t5_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:bottom;">R<sub>1</sub> = amino-alkyl-N-benzyl or alkyl-anilino substituents</th><th id="hd_h_ml307.t5_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:bottom;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu10.jpg" alt="Image ml307fu10.jpg" /></div></th></tr><tr><th headers="hd_h_ml307.t5_1_1_1_1" id="hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Entry</th><th headers="hd_h_ml307.t5_1_1_1_1" id="hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th headers="hd_h_ml307.t5_1_1_1_1" id="hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th><th headers="hd_h_ml307.t5_1_1_1_1" id="hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SBCCG ID</th><th headers="hd_h_ml307.t5_1_1_1_1" id="hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">S/P</th><th headers="hd_h_ml307.t5_1_1_1_1" id="hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Scaffold</th><th headers="hd_h_ml307.t5_1_1_1_2" id="hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R<sub>1</sub></th><th headers="hd_h_ml307.t5_1_1_1_2" id="hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"></th><th headers="hd_h_ml307.t5_1_1_1_2" id="hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">12<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912511</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49825946" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49825946</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0365097</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu11.jpg" alt="Image ml307fu11.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.62±1.06</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912511</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223054" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223054</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0365097</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.51±0.32</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">13<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912362</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49717789" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49717789</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0361072</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu12.jpg" alt="Image ml307fu12.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.37±1.33</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912362</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223050" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223050</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0361072</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.89±0.25</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="3" colspan="1" style="text-align:center;vertical-align:top;">14<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912338</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49723702" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49723702</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0362748</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu13.jpg" alt="Image ml307fu13.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.42±3.22</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912338</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223045" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223045</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0362748</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.28±1.18</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912338</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124384845" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">124384845</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0362748</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.18±0.58</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="4" colspan="1" style="text-align:center;vertical-align:top;">15<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912355</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49717716" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49717716</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367695</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="4" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="4" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu14.jpg" alt="Image ml307fu14.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.88±1.79</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912355</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415623" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415623</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367695</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.75±0.12</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912355</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223046" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223046</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367695</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.33±1.02</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912355</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415623" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415623</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367695</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.75±0.12</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="3" colspan="1" style="text-align:center;vertical-align:top;">16<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912274</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49734811" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49734811</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0366307</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu15.jpg" alt="Image ml307fu15.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.33±3.46</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912274</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223043" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223043</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0366307</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.92±0.6</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912274</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124384846" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">124384846</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0366307</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.57±0.61</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">17<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">20912356</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49717722" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49717722</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367820</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu16.jpg" alt="Image ml307fu16.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>20</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223047" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223047</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367820</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.31±1</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">18<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">20912360</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49717782" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49717782</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0369482</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu17.jpg" alt="Image ml307fu17.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>20</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223048" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223048</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0369482</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.31±0.79</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:top;">19<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">20912364</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49734860" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49734860</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0360846</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu18.jpg" alt="Image ml307fu18.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>20</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223051" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223051</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0360846</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.91±2.64</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16021607</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124384843" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">124384843</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0365273</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu19.jpg" alt="Image ml307fu19.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30.8±7.6</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">21<br />Screen Hit</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912340</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124384852" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">124384852</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0366303</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu20.jpg" alt="Image ml307fu20.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34.4±12.7</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912334</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124384844" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">124384844</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0366337</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu21.jpg" alt="Image ml307fu21.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22.7±7.86</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912361</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223049" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223049</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0446069</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu22.jpg" alt="Image ml307fu22.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.18±0.8</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16021605</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223058" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223058</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0446071</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu23.jpg" alt="Image ml307fu23.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46.3±5.14</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912574</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223059" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223059</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0446072</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu24.jpg" alt="Image ml307fu24.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14.7±1.99</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912576</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223060" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223060</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0446073</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu25.jpg" alt="Image ml307fu25.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.45±1.04</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912578</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223061" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223061</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0446074</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu26.jpg" alt="Image ml307fu26.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">53.7±41.5</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912332</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124384851" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">124384851</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0463034</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu27.jpg" alt="Image ml307fu27.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.66±1.23</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832466</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958958" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958958</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471612<br />R-Isomer</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu12.jpg" alt="Image ml307fu12.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.37±0.54</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832451</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958959" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958959</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471613<br />S-Isomer</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu12.jpg" alt="Image ml307fu12.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15±0.24</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">31</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832467</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958960" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958960</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471618</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu28.jpg" alt="Image ml307fu28.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">32</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832475</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958961" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958961</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471619</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">A</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu29.jpg" alt="Image ml307fu29.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.28±0.04</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832476</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958972" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958972</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471627</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu30.jpg" alt="Image ml307fu30.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.03±0.49</td></tr><tr><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912514</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415627" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415627</a></td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471610</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t5_1_1_1_1 hd_h_ml307.t5_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu31.jpg" alt="Image ml307fu31.jpg" /></div></td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t5_1_1_1_2 hd_h_ml307.t5_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">40.1±1.18</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml307t6"><div id="ml307.t6" class="table"><h3><span class="label">Table 6</span><span class="title">SAR Around Scaffold <b>B</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t6_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml307.t6_1_1_1_1" colspan="6" rowspan="1" style="text-align:left;vertical-align:bottom;">R<sub>1</sub> = N-Aryl amide substituents</th><th id="hd_h_ml307.t6_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:bottom;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu32.jpg" alt="Image ml307fu32.jpg" /></div></th></tr><tr><th headers="hd_h_ml307.t6_1_1_1_1" id="hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Entry</th><th headers="hd_h_ml307.t6_1_1_1_1" id="hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th headers="hd_h_ml307.t6_1_1_1_1" id="hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th><th headers="hd_h_ml307.t6_1_1_1_1" id="hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SBCCG ID</th><th headers="hd_h_ml307.t6_1_1_1_1" id="hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">S/P</th><th headers="hd_h_ml307.t6_1_1_1_1" id="hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Scaffold</th><th headers="hd_h_ml307.t6_1_1_1_2" id="hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R<sub>1</sub></th><th headers="hd_h_ml307.t6_1_1_1_2" id="hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">n</th><th headers="hd_h_ml307.t6_1_1_1_2" id="hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">35<br />Screen Hit</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">20912561</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/49724193" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">49724193</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0362591</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu33.jpg" alt="Image ml307fu33.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.87±5.32</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223056" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223056</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0362591</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.73±0.51</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912445</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223052" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223052</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0365095</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu34.jpg" alt="Image ml307fu34.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.95±1.24</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">37</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912440</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317312" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317312</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469607</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu35.jpg" alt="Image ml307fu35.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.69±2.38</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">38</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912446</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317314" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317314</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0367408</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu36.jpg" alt="Image ml307fu36.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">39</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16021815</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317315" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317315</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469609</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu37.jpg" alt="Image ml307fu37.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29.6±3.74</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">40</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912454</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317316" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317316</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469610</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu38.jpg" alt="Image ml307fu38.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">41</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912477</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317317" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317317</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469611</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu39.jpg" alt="Image ml307fu39.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912496</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317318" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317318</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469612</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu40.jpg" alt="Image ml307fu40.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">43</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912528</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317319" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317319</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469613</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu41.jpg" alt="Image ml307fu41.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">37.6±12.9</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912547</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317320" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317320</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469614</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu42.jpg" alt="Image ml307fu42.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28.7±29.2</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912558</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317321" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317321</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469615</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu43.jpg" alt="Image ml307fu43.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">46</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912563</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317322" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317322</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469616</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu44.jpg" alt="Image ml307fu44.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">48.2±2.46</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">47</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16021599</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/125317323" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">125317323</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469617</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu45.jpg" alt="Image ml307fu45.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18.6±7.92</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">48</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912444</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415624" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415624</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0469608</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu46.jpg" alt="Image ml307fu46.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24.5±0.17</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832461</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958964" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958964</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471620</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu47.jpg" alt="Image ml307fu47.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">50</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832464</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958966" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958966</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471621</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu48.jpg" alt="Image ml307fu48.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">51</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912564</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958967" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958967</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471622</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu49.jpg" alt="Image ml307fu49.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">58.7±0.42</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">52</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832458</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958968" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958968</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471623</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu50.jpg" alt="Image ml307fu50.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">53</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832477</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958969" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958969</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471624</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu51.jpg" alt="Image ml307fu51.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">54</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20912342</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958970" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958970</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471625</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu52.jpg" alt="Image ml307fu52.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">76.1±4.59</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">55</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16021755</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958971" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958971</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471626</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu53.jpg" alt="Image ml307fu53.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">72.8±2.33</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832452</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958973" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958973</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471628</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu54.jpg" alt="Image ml307fu54.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36.8±1.17</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">57</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639568</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415625" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415625</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471608</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu55.jpg" alt="Image ml307fu55.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">58</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639549</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415626" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415626</a></td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471609</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t6_1_1_1_1 hd_h_ml307.t6_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">B</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu56.jpg" alt="Image ml307fu56.jpg" /></div></td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t6_1_1_1_2 hd_h_ml307.t6_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23.8±0.47</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml307fu10"><div id="ml307.fu10" class="figure"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu57.jpg" alt="Image ml307fu57" /></div></div></article><article data-type="table-wrap" id="figobml307t7"><div id="ml307.t7" class="table"><h3><span class="label">Table 7</span><span class="title">SAR Around Scaffolds <b>C</b>, <b>D</b>, <b>E</b> and <b>F</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t7_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml307.t7_1_1_1_1" colspan="9" rowspan="1" style="text-align:left;vertical-align:bottom;">R<sub>1</sub> = N-Aryl amide & alkyl N-benzyl substituents<br />
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu58.jpg" alt="Image ml307fu58.jpg" /></div></th></tr><tr><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Entry</th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID</th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID</th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SBCCG ID</th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">S/P</th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Scaffold</th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R<sub>1</sub></th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"></th><th headers="hd_h_ml307.t7_1_1_1_1" id="hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">IC<sub>50</sub> (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">59</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56593287</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134225056" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134225056</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471521</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">E</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu59.jpg" alt="Image ml307fu59.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.04±0.04</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56593285</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134225057" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134225057</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471522</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">E</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu60.jpg" alt="Image ml307fu60.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.962±0.04</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">61</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56593276</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134225058" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134225058</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471523</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">E</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu61.jpg" alt="Image ml307fu61.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.79±0.21</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">62</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639566</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415614" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415614</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471524</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">E</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu62.jpg" alt="Image ml307fu62.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.74±0.99</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">63</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639564</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415615" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415615</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471600</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">D</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu63.jpg" alt="Image ml307fu63.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">52.6±7.28</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">64</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639540</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415616" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415616</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471601</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu62.jpg" alt="Image ml307fu62.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">65</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639551</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415617" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415617</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471602</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">D</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu64.jpg" alt="Image ml307fu64.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">72.3±9.82</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639552</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415618" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415618</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471603</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">D</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu55.jpg" alt="Image ml307fu55.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">79.5±0.3</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">67</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639559</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415619" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415619</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471604</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">D</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu65.jpg" alt="Image ml307fu65.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">32.8±1.5</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">68</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639554</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415620" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415620</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471605</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">D</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu66.jpg" alt="Image ml307fu66.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">27.2±0.71</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">69</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639532</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415621" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415621</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471606</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu67.jpg" alt="Image ml307fu67.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12.6±0.49</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">70</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639543</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415622</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471607<br /><b>S-Isomer</b></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">E</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu67.jpg" alt="Image ml307fu67.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.66±0.22</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">71</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56639556</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134415628" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134415628</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471611<br /><b>R-Isomer</b></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">E</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu67.jpg" alt="Image ml307fu67.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.781±0.01</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">72</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832457</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958974</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471629</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu62.jpg" alt="Image ml307fu62.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91.2±2.44</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">73</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832460</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958975" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958975</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471630</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu68.jpg" alt="Image ml307fu68.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">42.6±0.74</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">74</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832462</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958976" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958976</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471631</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu69.jpg" alt="Image ml307fu69.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">32.2±1.53</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">75</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832454</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958977" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958977</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471632</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu42.jpg" alt="Image ml307fu42.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">32.6±1.09</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">76</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832471</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958978" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958978</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471633</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu70.jpg" alt="Image ml307fu70.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">77.1±0.48</td></tr><tr><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">77</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">56832468</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134958979" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134958979</a></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS-0471634</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143542/bin/ml307fu60.jpg" alt="Image ml307fu60.jpg" /></div></td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml307.t7_1_1_1_1 hd_h_ml307.t7_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>100</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml307t8"><div id="ml307.t8" class="table"><h3><span class="label">Table 8</span><span class="title">Summary of <i>in vitro</i> ADME Properties of UBC13 inhibitor probe ML307</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143542/table/ml307.t8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml307.t8_lrgtbl__"><table class="no_margin"><tbody><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in pION’s buffer (μg/mL) <i>[μM]</i><sup>a</sup> pH 5.0/6.2/7.4</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">197.9/205.6/211.8 <i>[348/351/373]</i></td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in 1× PBS, pH 7.4 (μg/mL) <i>[μM]</i><sup>a</sup></td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">199.9 [<i>352]</i></td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>PAMPA Permeability</b>, P<sub>e</sub> (x10<sup>−6</sup> cm/s) Donor pH: 5.0/6.2/7.4 Acceptor pH: 7.4</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">68/523/776<sup>*</sup></td></tr><tr><td rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Protein Binding</b> (% Bound)</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human 1 μM/10 μM</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99.66/98.65</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Mouse 1 μM/10 μM</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">95.73/91.51</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Stability in 1X PBS (pH 7.4)/1:1 PBS: ACN</b> (% Remaining at 48 hr, ambient temp)</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">80.51/100</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Stability</b> (%Remaining at 3 hrs) Human/Mouse</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">95.51/96.30</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Hepatic Microsome Stability</b> (% Remaining at 1hr) Human/Mouse</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.14/0.13</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Toxicity</b> Towards Fa2N-4 Immortalized Human Hepatocytes LC<sub>50</sub> (μM)</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml307.tfn1"><p class="no_margin">Solubility also expressed in molar units (μM) as indicated in <i>italicized [bracketed values],</i> in addition to more traditional μg/mL units.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml307fu11"><div id="ml307.fu11" class="figure"><div class="graphic"><img data-src="/books/NBK143542/bin/ml307fu71.jpg" alt="Image ml307fu71" /></div></div></article><article data-type="fig" id="figobml307fu12"><div id="ml307.fu12" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=1H%20NMR%20Spectrum%20of%20ML307%20(500%20MHz%2C%20CDCl3).&p=BOOKS&id=143542_ml307fu72.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK143542/bin/ml307fu72.jpg" alt="1H NMR Spectrum of ML307 (500 MHz, CDCl3)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title"><sup>1</sup>H NMR Spectrum of ML307 (500 MHz, CDCl<sub>3</sub>)</span></h3></div></article><article data-type="fig" id="figobml307fu13"><div id="ml307.fu13" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=LC-MS%20for%20ML307.&p=BOOKS&id=143542_ml307fu73.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK143542/bin/ml307fu73.jpg" alt="LC-MS for ML307." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">LC-MS for ML307</span></h3><div class="caption"><p>(Reverse phase C18 column: isocratic)</p></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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